Geminally substituted cyanoethylpyrazolo pyridones as janus kinase inhibitors

ABSTRACT

The instant invention provides compounds of Formula (I) which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.

BACKGROUND OF THE INVENTION

Protein kinases are a group of enzymes that regulate the activity of their target proteins by the addition of phosphate groups to the protein substrate. Kinases play an essential role in many physiological processes including cell division, differentiation, cellular homeostasis and signal transduction. Kinases can be subdivided by their target into Serine/Threonine kinases and Tyrosine kinases. Tyrosine kinases are further subdivided into receptor tyrosine kinases and non-receptor tyrosine kinases. The mammalian Janus kinase (JAK) family members are non-receptor tyrosine kinases.

The JAK family has four members; JAK1, JAK2, JAK3 and TYK2. JAK1, JAK2 and TYK2 are universally expressed, whereas JAK3 expression is limited to hematopoetic cells. The JAK family is involved in intracellular signal transduction from >70 different cytokines Cytokines bind to their cell surface receptors resulting in receptor dimerization and subsequent activation/phosphorylation of JAK tyrosine kinases. The JAKs are either constitutively associated with the receptor or are recruited upon cytokine binding. Specific tyrosine residues on the receptor are then phosphorylated by activated JAKs and serve as docking sites for STAT proteins. STATs are phosphorylated by JAKs, dimerize, then translocate to the nucleus where they bind specific DNA elements and activate gene transcription. JAK1 signals in conjunction with all JAK isoforms in a cytokine dependent manner.

JAKs are essential for multiple physiological functions. This has been demonstrated using genetically engineered mouse models that are deficient in specific JAKs. Jak1^(−/−) mice die perinatally, while Jak2^(−/−) mice have deficiencies in erythropoesis and die around day E12. Jak3^(−/−) mice are viable, but have a SCID phenotype with deficiencies in T cells, B cells and NK cells. TYK2^(−/−) mice exhibit features of hyper IgE syndrome. These phenotypes demonstrate the essential and non-redundant roles of JAK activity in vivo (K. Ghoreschi, A. Laurence, J. J. O'Shea, Immunol. Rev. 228, 273 (2009)).

Furthermore, mutations in the JAK enzymes have been associated with diseases in humans. Inactivating mutations in JAK3 (or the cognate common gamma chain cytokine receptor) cause a severe SCID phenotype (J. J. O'Shea, M. Pesu, D. C. Borie, P. S. Changelian, Nat. Rev. Drug Discov. 3, 555 (2004)). Deletions of TYK2 result in hyper IgG syndrome and increased infection risk (Y. Minegishi et al., Immunity. 25, 745 (2006)). No inactivating mutations have been reported for JAK1 or JAK2, consistent with the data from mice that demonstrates that JAK1 and JAK2 deficient mice are not viable. However, several mutations that result in constitutively active JAK2 have been identified, resulting in myeloproliferative diseases and confirming the central role of JAK2 in hematopoesis (O. bdel-Wahab, Curr. Opin. Hematol. 18, 117 (2011)). JAK2 is the sole JAK family member involved in signal transduction of the critical hematopoetic cytokines IL-3, GMCSF, EPO and TPO.

The wealth of mouse and human genetic data demonstrating a central role for JAK kinase activity in autoimmune disease, hematopoesis and oncology has been supported by the use of pan-JAK inhibitors in clinical trials for autoimmune diseases and neoplasms (See K. Ghoreschi, et al, Immunol. Rev. 228, 273 (2009), and A. Quintas-Cardama, H. Kantarjian, J. Cortes, S. Verstovsek, Nat. Rev. Drug Discov. 10, 127 (2011)).

A considerable body of literature has accumulated that link the Jak/STAT pathway to various diseases and disorders including hyperproliferative disorders and cancer such as leukemia and lymphomas, immunological and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, type I diabetes, amyotropic lateral sclerosis and multiple sclerosis.

SUMMARY OF THE INVENTION

The present invention provides novel compounds which are inhibitors of JAKs. The invention also provides a method for the treatment and prevention of JAK-mediated diseases and disorders using the novel compounds, as well as pharmaceutical compositions containing the compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula I or pharmaceutically acceptable salts, or stereoisomers thereof:

-   A is selected from aryl, heteroaryl, cycloalkylC₍₀₋₁₀₎alkyl, C₁₋₆     alkyl; -   R² and R³ are each independently selected from hydrogen, C₁₋₄ alkyl     and hydroxy, wherein R² and R³ may optionally, join together with     the carbon they are attached to form a 3 to 6 membered ring; -   X₁ is C; -   X₂, X₃, and X₄ are each independently selected from O, N, S, and C     and provided that the formed ring system contains 0, 1, 2, or 3     atoms selected from O, N and S; -   n is 0, 1, 2, 3 or 4; -   m is 0, 1, 2, 3 or 4; -   p is 0, 1, 2, 3, or 4; -   R⁴ is selected from:     -   halogen,     -   oxo (═O),     -   C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀         alkyl,     -   C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl,     -   C₁₋₁₀ alkylamino(carbonyl)₀₋₁C₀₋₁₀alkyl,     -   (C₁₋₁₀)heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁aminoC₀₋₁₀alkyl,     -   (C₁₋₁₀)heteroalkylamino(carbonyl)₀₋₁C₀₋₁₀alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   C₁₋₁₀ alkylsulfonyl,     -   C₁₋₁₀ heteroalkylsulfonyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl,     -   heteroarylC₀₋₁₀ alkylsulfonyl,     -   arylC₀₋₁₀ alkylsulfonyl,     -   —SO₂NH₂,     -   —SO₂NH(C₁₋₆alkyl),     -   —SO₂N(C₁₋₆alkyl)₂,     -   C₀₋₁₀ alkylsulfamoyl,     -   C₁₋₁₀ heteroalkylsulfamoyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl,     -   heteroarylC₀₋₁₀ alkylsulfamoyl,     -   arylC₀₋₁₀ alkylsulfamoyl,     -   C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonimidoylC₀₋₁₀ alkyl,     -   heteroarylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   arylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   (C₁₋₁₀ alkyl)₁₋₂amino,     -   —CO₂(C₀₋₁₀ alkyl),     -   —(C₀₋₁₀ alkyl)CO₂H,     -   —SO₂CF₃,     -   —SO₂CF₂H,     -   —SO₂CH₂CF₃,     -   C₁₋₁₀ alkylsulfinyl,     -   C₁₋₄acylaminoC₀₋₁₀ alkyl,     -   hydroxy,     -   —(C₁₋₁₀ alkyl)OH,     -   C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano,     -   (C₁₋₆alkyl)cyano, and     -   C₁₋₆haloalkyl,         wherein two R⁴ together with the ring atom to which each is         attached optionally may form a saturated ring; -   R⁵ is selected from:     -   halogen,     -   oxo (═O),     -   C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀         alkyl,     -   C₀₋₁₀ alkylaminocarbonylC₀₋₁₀alkyl,     -   C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl,     -   (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   (C₁₋₁₀ alkyl)₁₋₂ amino,     -   —SF₅,     -   C₀₋₁₀ alkylsulfonyl,     -   C₁₋₁₀ heteroalkylsulfonyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl,     -   heteroarylC₀₋₁₀ alkylsulfonyl,     -   arylC₀₋₁₀ alkylsulfonyl,     -   C₀₋₁₀ alkylsulfamoyl,     -   C₁₋₁₀ heteroalkylsulfamoyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl,     -   heteroarylC₀₋₁₀ alkylsulfamoyl,     -   C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonimidoylC₀₋₁₀ alkyl,     -   heteroarylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   arylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl,     -   —SO₂NH₂,     -   —SO₂NH(C₁₋₆alkyl),     -   —SO₂N(C₁₋₆alkyl)₂,     -   arylC₀₋₁₀ alkylsulfamoyl,     -   (C₀₋₁₀ alkyl)₁₋₂ amino,     -   —CO₂(C₀₋₁₀ alkyl),     -   —(C₀₋₁₀ alkyl)CO₂H,     -   —SO₂CF₃,     -   —SO₂CF₂H,     -   —SO₂CH₂CF₃,     -   C₁₋₁₀ alkylsulfinyl,     -   C₁₋₄acylaminoC₀₋₁₀ alkyl, hydroxy,     -   —(C₁₋₁₀ alkyl)OH,     -   C₁₋₁₀ alkoxyC₀₋₁₀ alkyl,     -   cyano,     -   (C₁₋₆alkyl)cyano, and     -   C₁₋₆haloalkyl; and         wherein R⁴ and R⁵ are each optionally substituted with 1, 2, 3,         or 4 R⁶ substituents and R⁶ is independently selected from:     -   halogen,     -   C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁ C₀₋₁₀         alkyl,     -   C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl (carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,     -   (C₃₋₁₂)cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   heteroarylC₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy,     -   aryl (C₀₋₁₀)alkylaminocarbonyloxy,     -   —CO₂(C₀₋₁₀ alkyl),     -   —(C₀₋₁₀ alkyl)CO₂H,     -   oxo (═O),     -   C₀₋₁₀ alkylsulfonyl,     -   C₁₋₁₀ heteroalkylsulfonyl,     -   (C₃₋₁₂) cycloalkylsulfonyl,     -   (C₃₋₁₂) cycloheteroalkylsulfonyl,     -   heteroarylsulfonyl,     -   arylsulfonyl,     -   aminosulfonyl,     -   —SO₂NH₂,     -   —SO₂NH(C₁₋₆alkyl),     -   —SO₂N(C₁₋₆alkyl)₂,     -   —SO₂CF₃,     -   —SO₂CF₂H,     -   C₁₋₁₀ alkylsulfinyl,     -   amino,     -   (C₁₋₁₀ alkyl)₁₋₂amino,     -   -(oxy)₀₋₁(carbonyl)₀₋₁N(C₀₋₁₀ alkyl)₁₋₂     -   C₁₋₄acylaminoC₀₋₁₀ alkyl,     -   hydroxy,     -   (C₁₋₁₀ alkyl)OH,     -   C₁₋₁₀ alkoxyC₀₋₁₀ alkyl,     -   (C₁₋₁₀ alkyl)cyano,     -   cyano, and     -   C₁₋₆haloalkyl; and

R⁶ is optionally substituted with 1, 2, or 3 R⁷ substituents selected from hydrogen, hydroxy, (C₁₋₆)alkyl, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, oxo (O═), aminosulfonyl, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —C₁₋₁₀ alkylsulfinyl, —O₍₀₋₁₎(C₁₋₁₀)halo, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, alkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂

Representative compounds of the instant invention include, but are not limited to the following compounds and their pharmaceutically acceptable salts and stereoisomers thereof:

-   tert-butyl     3-(cyanomethyl)-3-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-[3-(ethylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{3-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-[3-(cyclobutylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-[3-(ethylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]azetidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-[3-(methylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-[3-(cyclopropylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]azetidine-1-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-(4-oxo-3-((2-(trifluoromethyl)pyridin-4-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-(3((4(methoxycarbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-(3-((4-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-[4-oxo-3-({4-[2,2,2-trifluoro-hydroxyethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{4-oxo-3-[(4-sulfamoylphenyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-{[1-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-3-fluoro-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{3-[(2-methyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-{[4-(pentafluorosulfanyl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-{[4-(trifluoromethyl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-3-fluoro-4-{3-[(2-methyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-3-methyl-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-((1-oxo-2,3-dihydro-1H-inden-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-     carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-{[3-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-3-fluoro-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-{[4-(dimethylsulfamoyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluoropiperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-3-fluoro-4-[4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-3-fluoro-4-[4-oxo-3-({4-[2,2,2-trifluoro-1-hydroxyethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   tert-butyl     4-{3-[(2-tert-butyl-1,12-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; -   tert-butyl     4-{3-[(2-tert-butyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-{[1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1,2-benzisothiazol-5-yl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluoropiperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   2-(4-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)acetonitrile; -   2-(3-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   4-((1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   2-(3-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   methyl     5-(cyanomethyl)-5-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-     carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-{3-[(2-fluoropyridin-4-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}azetidine-1-carboxylate; -   tert-butyl     3-(cyanomethyl)-3-[4-oxo-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]azetidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     5-(3-((4-1-amino-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   N-(tert-butyl)-4-((1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzenesulfonamide; -   2-(1-(2,2-difluoropropanoyl)-4-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; -   N-(tert-butyl)-4-((1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; -   2-(4-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)acetonitrile; -   tert-butyl     4-(3-(3,5-bis((1H-pyrazol-1-yl)methyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-(3,5-dimethylphenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(3-(3,5-bis((1H-1,2,3-triazol-1-yl)methyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(3-(3,5-bis((2H-1,2,3-triazol-2-yl)methyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(3-(3-((1H-1,2,3-triazol-1-yl)methyl)-5-((2H-1,2,3-triazol-2-yl)methyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(3-(m-toluidino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-(isoindolin-5-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-{[2-(cyclopropylmethyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{3-[(2-ethyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-[3-[(2-methyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   methyl     4-{3-[(2-tert-butyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   methyl     4-{3-[(2-ethyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-{[2-(2-methylpropyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-{[2-(cyclopropylmethyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-{[2-(cyclopentylmethyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-[4-oxo-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{3-[(2-fluoropyridin-4-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   4-(1-(1-(cyanomethyl)cyclohexyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-ylamino)-N,N-dimethylbenzenesulfonamide; -   2-(1-(3-((2-(tert-butyl)-1,     1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-     yl)cyclohexyl)acetonitrile; -   tert-butyl     4-(cyanomethyl)-4-(3-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   2-(8-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,4-dioxaspiro[4.5]decan-8-yl)acetonitrile; -   4-({-[1-(cyanomethyl)-2-fluorocyclohexyl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   {2-fluoro-1-[4-oxo-3-({4-[2,2,2-trifluoro-1-hydroxy-1-methylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]cyclohexyl}acetonitrile -   {2-fluoro-1-[3-({4-[(1-methylethyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]cyclohexyl}acetonitrile; -   2-(1-(3-((4-(1-amino-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   tert-butyl     5-(3-((4-(N-(tert-butyl)-N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(N-isopropyl-N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(N-ethyl-N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate;     -   tert-butyl         5-(3-((4-((1H-1,2,3-triazol-1-yl)methyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(3-((4-((2H-1,2,3-triazol-2-yl)methyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(cyclopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(3-((2-(tert-butyl)-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-cyclohexyl-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-     pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-cyclopentyl-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(3-((4-(1-amino-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   [3-(3-{[4-(azetidin-1-ylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; -   {3-[3-({4-[(3-methylazetidin-1-yl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   {3-[3-({4-[(2,2-dimethylpyrrolidin-1-yl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   [3-{3-[(4-{[2-methylazetidin-1-yl]sulfonyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; -   {3-[4-oxo-3-({4-[2,2,2-trifluoro-1-hydroxy-1-methylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   ethyl     3-(4-((1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)phenyl)-4,4,4-trifluoro-3-hydroxy-2,2-dimethylbutanoate; -   2-(3-(3-((4-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((4-(3-fluoropyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((4-(3-methoxypyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((4-(3-methoxypyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((1-hydroxy-2,2-dimethyl-1-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(1-(3-((2-(tert-butyl)-1,     1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   2-(1-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzonitrile; -   2-(1-(4-oxo-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   (1-{3-[(3,3-dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}cyclopentyl)acetonitrile; -   tert-butyl     4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzoate; -   4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzamide; -   2-(1-(3-((2-isopropyl-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-isopropylbenzenesulfonamide; -   4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; -   2-(1-(3-((4-(azetidin-1-ylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   2-(1-(3-((4-(ethylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   N-(tert-butyl)-4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; -   N-(tert-butyl)-4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-ethylbenzenesulfonamide; -   4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-diethylbenzenesulfonamide; -   tert-butyl     2-(4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylphenylsulfonamido)-2-methylpropanoate; -   2-(1-(4-oxo-3-((1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; -   ethyl     2-(4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylphenylsulfonamido)-2-methylpropanoate; -   tert-butyl     2-(5-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-1-oxoisoindolin-2-yl)-2-methylpropanoate; -   methyl     4-(cyanomethyl)-4-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-((1-hydroxy-1-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-((4-cyanophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-((4-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(4-oxo-3-(quinolin-6-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   2-(2-fluoro-1-(3-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(2-fluoro-1-(3-((2-fluoropyridin-4-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-fluorocyclohexyl)acetonitrile; -   2-(2-fluoro-1-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-     yl)cyclohexyl)acetonitrile; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(thiazolidine-3-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(2-methylthiazolidine-3-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(2-methylthiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxy-4-isopropoxy-3,3-dimethyl-4-oxobutan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((1-hydroxy-2,2-dimethyl-1-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxy-3,3-dimethylbutan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-methoxypropan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   {1-[3-({4-[1-(ethylamino)-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-2-fluorocyclohexyl}acetonitrile; -   [2-fluoro-1-{3-[(4-{1-methyl-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-     yl}cyclohexyl]acetonitrile; -   {1-[3-({4-[1-amino-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-2-fluorocyclohexyl}acetonitrile; -   [3-{3-[(2-tert-butyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; -   {3-[3-({4-[(1-methylethyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   4-({1-[3-(cyanomethyl)-4-fluorotetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   N-tert-butyl-4-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N-methylbenzenesulfonamide; -   [3-(3-{[4-(tert-butylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; -   N-tert-butyl-4-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)benzenesulfonamide; -   tert-butyl[5-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-1,1-dioxido-1,2-benzisothiazol-2(3H)-yl]acetate; -   tert-butyl     3-{[4-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)phenyl]sulfonyl}-3-methylbutanoate; -   {3-[3-({4-[1-amino-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   {3-[3-({4-[1-(tert-butylamino)-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   [3-(3-{[4-(cyclopentylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; -   {3-[4-oxo-3-({4-[(1,1,2-trimethylpropyl)sulfonyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   [3-(3-{[4-(cyclohexylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; -   tert-butyl     5-(3-((4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-     (cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   {3-[3-({4-[(1,1-dimethylpropyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   [3-{3-[(2-cyclopentyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; -   {3-[4-oxo-3-({4-[2,2,2-trifluoro-1-pyrrolidin-1-ylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   {3-[4-oxo-3-({4-[1-pyrrolidin-1-ylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   {3-[3-({4-[(2,2-dimethylcyclopentyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(morpholinosulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   [3-(3-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; -   [3-{4-oxo-3-[(4-{2,2,2-trifluoro-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(1-(ethylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-(isopropylamino)ethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(1-(pyrrolidin-1-yl)ethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-     pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(1-(dimethylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-(quinolin-6-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-cyanoquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-methylquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(1H-pyrazol-1-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(2,2-dimethylmorpholine-4-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-(quinolin-3-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-(dimethylamino)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(3-((2-carbamoylquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   2-(3-(4-oxo-3-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((2-(dimethylamino)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((2-methylquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-morpholinoquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-(2-methylmorpholino)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(3-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(propan-2-yl-(S or     R)-sulfonimidoyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   2-(3-(4-oxo-3-((4-(propan-2-yl-(S or     R)-sulfonimidoyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   4-({1-[1-(cyanomethyl)-2-fluorocyclohexyl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   tert-butyl     5-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(cyclopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-(dimethylcarbamoyl)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   4-({1-[3-(cyanomethyl)tetrahydrofuran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)benzonitrile; -   [3-{3-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydrofuran-3-yl]acetonitrile; -   [3-{3-[(4-chloro-8-fluoroquinolin-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydrofuran-3-yl]acetonitrile; -   [3-{3-[(4-fluoroquinolin-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydrofuran-3-yl]acetonitrile; -   (3-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydrofuran-     3-yl)acetonitrile; -   2-(3-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydrofuran-3-yl)acetonitrile; -   2-(4-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-4-yl)acetonitrile; -   2-(4-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-4-yl)acetonitrile; -   N-(tert-butyl)-4-((1-(4-(cyanomethyl)tetrahydro-2H-pyran-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; -   4-((1-(4-(cyanomethyl)tetrahydro-2H-pyran-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   2-(4-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; -   2-(3-fluoro-4-(3-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-tetrahydro-2H-pyran-4-yl)acetonitrile; -   2-(4-(3-((2-(tert-butyl)-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; -   2-(3-fluoro-4-(3-(3-methyl-4-(thiomorpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-tetrahydro-2H-pyran-4-yl)acetonitrile; -   2-(3-fluoro-4-(4-oxo-3-((4-(2-(trifluoromethyl)piperidin-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-4-yl)acetonitrile; -   2-(4-(3-((4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; -   2-[4-(3-{[1,1-dioxo-2-(piperidin-4-yl)-3H-1,2-benzothiazol-5-yl]amino}-4-oxo-5H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorooxan-4-yl]acetonitrile; -   tert-butyl-4-(cyanomethyl)-3-fluoro-4-{3-[(4-{1-methyl-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(2-(isopropylamino)propan-2-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl-4-(cyanomethyl)-3-fluoro-4-(3-{[4-(1-methoxyethyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{3-[(4-{1-methyl-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   2-(4-(3-((1,1-dioxido-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; -   tert-butyl     4-(cyanomethyl)-3-fluoro-4-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(3-((4-(1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-((4-(3-(trifluoromethyl)pyrrolidin-3-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(3-(trifluoromethyl)pyrrolidin-3-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-((S or     R)-2-(trifluoromethyl)piperidin-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-((4-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(N-isopropylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(3-((4-(N-benzylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl 4-(cyanomethyl)-4-(3-((4-(N-(cyclopropylmethyl)     sulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(N-(2-methoxyethyl)sulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(N-cyclohexylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-((4-(piperidin-1-ylsulfonyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-     carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(morpholinosulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((3-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(N-(cyclopropylmethyl)sulfamoyl)-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   (4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl)acetonitrile; -   [1-(cyclopropylcarbonyl)-4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl]acetonitrile; -   4-({1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(4-methylbenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[4-(1-methylethyl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[4-(1-methylethyl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzene     sulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[4-(1methylethoxy)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzene     sulfonamide; -   4-({1-[4-(cyanomethyl)-1-(4-fluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(3-fluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzene     sulfonamide; -   4-({1-[4-(cyanomethyl)-1-(2-fluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(2,6-difluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzene     sulfonamide; -   4-({1-[4-(cyanomethyl)-1-(2,3,6-trifluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(1,3-oxazol-2-ylmethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(4-isoxazol-3-ylbenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[4-(2-oxopyrrolidin-1-yl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-     yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(3-phenylpropyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzene     sulfonamide; -   4-({1-[4-(cyanomethyl)-1-(1H-indol-4-ylmethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-((1-(4-(cyanomethyl)-1-(1-(2,6-difluorophenyl)ethyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   4-((1-(4-(cyanomethyl)-1-phenethylpiperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   3-({1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-propanoylpiperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(methoxyacetyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(N,N-dimethylglycyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(cyclopropylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[(3,3-difluorocyclobutyl)carbonyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-     N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(cyclohexylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[tricyclo[3.3.1.13,7]dec-1-ylcarbonyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(cyclopropylacetyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(3-cyclopropylpropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(phenylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-[(1-{1-[(4-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-[(1-{1-[(3-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-[(1-{1-[(2-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-{[4-(trifluoromethyl)phenyl]acetyl}piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(3-phenylpropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(2,3-dihydro-1H-inden-2-ylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-[(1-{4-(cyanomethyl)-1-[(2-oxopyrrolidin-1-yl)acetyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(3-cyanopropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-({1-[4-(cyanomethyl)-1-(3,3-dimethylbutanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; -   4-((1-(4-(cyanomethyl)-1-(2-(methylthio)propanoyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   4-((1-(1-(2-cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   methyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   phenyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   4-fluorophenyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   neopentyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   ethyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   isopropyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   2-methylcyclopentyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   2-(methylthio)ethyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tetrahydro-2H-thiopyran-4-yl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   1-methoxypropan-2-yl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tetrahydrofuran-3-yl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tetrahydro-2H-pyran-4-yl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   1,1,1-trifluoropropan-2-yl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   1-(pyridin-2-yl)ethyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   1-cyanoethyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tetrahydrofuran-3-yl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   2,2,2-trifluoroethyl     4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   isopropyl-4-(cyanomethyl)-4-(3-(2-fluoropyridin-4-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   methyl     4-(cyanomethyl)-4-(3-(2-fluoropyridin-4-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   4-((1-(4-(cyanomethyl)-1-((2,2,2-trifluoroethyl)sulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   4-((1-(4-(cyanomethyl)-1-(cyclopropylsulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; -   6-(4-(cyanomethyl)-4-(3-((4(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; -   6-(4-(cyanomethyl)-4-(3-((4((difluoromethyl)sulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; -   2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(5     (trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; -   6-(4-(cyanomethyl)-4-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; -   6-((3R,4R)-4-(cyanomethyl)-3-fluoro-4-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; -   2-(1-(5-iodopyridin-2-yl)-4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; -   2-(1-(5-bromopyridin-2-yl)-4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; -   2-(4-(3-(3-methyl-4-(thiomorpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; -   2-(4-(4-oxo-3-(4-(2,2,2-trifluoro-1-hydroxyethyl)phenylamino)-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; -   2-(4-(3-(4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; -   2-(1-(2,2-difluoropropanoyl)-4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; -   2-(4-(3-fluoroazetidin-1-yl)-1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; -   2-(4-hydroxy-1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-methoxyazetidin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)acetonitrile; -   2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-hydroxycyclohexyl)acetonitrile; -   2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; -   2-(4-(3-methoxyazetidin-1-yl)-1-(4-oxo-3-((4-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(4-oxo-3-((4-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; -   2-(4-(cyclohexylamino)-1-(4-oxo-3-((4-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((4-chloro-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyclohexylamino)cyclohexyl)acetonitrile; -   2-(1-(3-((4-chloro-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-methoxyazetidin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((4-chloro-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; -   2-(1-(3-((4-((difluoromethyl)sulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)acetonitrile; -   4-((1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   2-(4-(3-fluoroazetidin-1-yl)-1-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(4-(dimethylamino)-1-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo-[d]isothiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(4-(3-fluoroazetidin-1-yl)-1-(3-((2-methyl-1,1-dioxido-2,3-dihy-drobenzo[d]isothiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; -   2-(1-(3-((2-(tert-butyl)-1,     1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(dimethylamino)cyclohexyl)acetonitrile; -   4-((1-(1-(cyanomethyl)-4-oxocyclohexyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; -   N-(tert-butyl)-5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxamide; -   N-tert-butyl-5-{3-[(2-tert-butyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-5-(cyanomethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide; -   isopropyl     5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   2-(3-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((3-methyl-4-(2-methylpiperidine-1-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((3-methyl-4-(2-methylpiperidine-1-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   2-(3-(3-((4-(4-hydroxy-4-methylpiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(pyrrolidine-1-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(3-methylmorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(2,6-dimethylmorpholine-4-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((4-(ethyl(2,2,2-trifluoroethyl)carbamoyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((3-methyl-4-(methyl(2,2,2-trifluoroethyl)carbamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(3-((4-(2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-methylbenzo[d]thiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   [1-{3-[(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-2-fluorocyclohexyl]acetonitrile; -   (tert-butyl     5-(cyanomethyl)-5-(3-((3,3-dimethyl-2-oxoindolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-     pyran-2-carboxylate; -   [3-{3-[(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; -   [3-{3-[(2-methyl-1,3-benzothiazol-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; -   tert-butyl     5-(cyanomethyl)-5-(3-((2-fluoropyridin-4-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl-4-(3-((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-{3-[(5-methyl-4-{3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl}cyclohexa-1,3,5-trien-1-yl)amino]-4-oxo-5H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; -   tert-butyl-4-(cyanomethyl)-4-(3-(3-methyl-4-(thiomorpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl-4-(cyanomethyl)-4-(3-((1,1-dioxido-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-(4-(2-(trifluoromethyl)piperidin-2-yl)phenylamino)-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(4-oxo-3-(4-(2-(trifluoromethyl)pyrrolidin-2-yl)phenylamino)-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   tert-butyl     4-(cyanomethyl)-4-(3-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; -   5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N-(methylsulfonyl)tetrahydro-2H-pyran-2-carboxamide; -   5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N,N-dimethyltetrahydro-2H-pyran-2-carboxamide;     and -   2-(3-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)acetonitrile.

The invention also encompasses pharmaceutical compositions containing a compound of Formula I, and methods for treatment or prevention of JAK mediated diseases using compounds of Formula I.

The invention is described using the following definitions unless otherwise indicated.

As used herein except where noted, “alkyl” is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by “Me” or CH₃, ethyl may be represented by “Et” or CH₂CH₃, propyl may be represented by “Pr” or CH₂CH₂CH₃, butyl may be represented by “Bu” or CH₂CH₂CH₂CH₃, etc. “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. C₁₋₆ alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. “C₁₋₄ alkyl” means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term “alkylene” refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments. For illustration, the term “unsubstituted A-C₄alkylene-B” represents A-CH₂—CH₂—CH₂—CH₂—B.

The term “alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.

“Acyl” means a —C(O)R radical where R is optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl heteroaryl, etc.

“Acylamino” means a —NRR′ radical where R is H, OH, or alkoxy and R′ is acyl, as defined herein.

The term “alkyl” refers to an aliphatic hydrocarbon group which may be straight or branched and having the indicated number of carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, and the like.

The term “heteroalkyl” refers to an alkyl group where 1, 2, or 3 of the carbon atoms is substituted by a heteroatom independently chosen from N, O, or S.

“Alkenyl” refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and having the indicated number of carbon atoms. Preferably alkenyl contains one carbon to carbon double bond, and up to four nonaromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-1-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkynyl” refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and having the indicated number of carbon atoms. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.

“Alkoxy” refers to an alkyl-O— group in which the alkyl group is as described above. C₁₋₆alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

“Alkoxyalkyl” refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by alkoxy groups. Examples include CH₂OCH₃, CH₂CH₂OCH₃ and CH(OCH₃)CH₃.

“Aminoalkyl” refers to an alkyl group as described above in which one hydrogen atom has been replaced by an amino, monoalkylamino or dialkylamino group. Examples include CH₂NH₂, CH₂CH₂NHCH₃ and CH(N(CH₃)₂)CH₃.

The term “C₀” as employed in expressions such as “C₀₋₆ alkyl” means a direct covalent bond; or when the term appears at the terminus of a substituent, C₀₋₆ alkyl means hydrogen or C₁₋₆alkyl. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond. For example, in the structure

wherein s is an integer equal to zero, 1 or 2, the structure is

when s is zero.

The term “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms “C₃₋₇ cycloalkyl”, “C₃₋₆ cycloalkyl”, “C₅₋₇ cycloalkyl” and the like have analogous meanings.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).

The term “aryl” refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, 2,3-dihydro-1H-indenyl, and biphenyl.

The term “carbocycle” (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C₃ to C₈ monocyclic, saturated or unsaturated ring or (ii) a C₇ to C₁₂ bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term “fused bicyclic carbocycle” generally refers to a C₇ to C₁₀ bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. Unless otherwise noted, carbocycle is unsubstituted or substituted with C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, aryl, halogen, NH₂ or OH. A subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:

“Cyanoalkyl” refers to an alkyl group as described above in which one hydrogen atom has been replaced by a cyano group. Examples include CH₂CN, CH₂CH₂CN and CH(CN)CH₃.

“Cycloalkyl” means a carbocyclic ring system having 3 to 12 ring carbon atoms; said ring system may be (a) a monocyclic saturated carbocycle optionally fused to a benzene or a partially unsaturated carbocycle, or (b) a bicyclic saturated carbocycle. For a bicyclic system, within either (a) or (b), the rings are fused across two adjacent ring carbon atoms (e.g., decalin), at one ring carbon atom (e.g., spiro[2.2]pentane), or are bridged groups (e.g., norbornane). Additional examples within the above meaning include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, perhydroindan, decalin, spiro[4.5]decane, bicyclo[2.2.2]octane, and the like.

“Haloalkyl” refers to an alkyl group as described above wherein one or more (in particular 1 to 5) hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. C₁₋₆haloalkyl, for example, includes —CF₃, —CF₂CF₃, CHFCH₃, and the like.

“Heterocycle”, “heterocyclic” or “heterocyclyl” represents a monocyclic or bicyclic 3-12 membered ring system in which at least one ring is non-aromatic (saturated or partially unsaturated) and containing at least one heteroatom selected from O, S and N. In a bicyclic ring system, the second ring may be a heteroaryl, heterocycle or a saturated, partially unsaturated or aromatic carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring. For a bicyclic system, the rings may be fused across two adjacent ring atoms (e.g., quinoline), at one ring carbon atom (e.g., 1,4-dioxaspiro[4.5]decane), or are bridged groups (e.g. 8-azabicyclo[3.2.1]octanyl,). “Heterocyclyl” therefore includes heteroaryls, as well as dihydro and tetrathydro analogs thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.

Examples of heterocycles (heterocyclyl) include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, dihydroimidazolyl, dihydroindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 2,3-dihydrobenzofuranyl, benzo-1,4-dioxanyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof.

Saturated heterocyclics form a subset of the heterocycles; i.e., the terms “saturated heterocyclic and (C₃₋₁₂)heterocycloalkyl” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated. The term “saturated heterocyclic ring” refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).

Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system. The term “heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S. For a bicyclic heteroaryl only one of the rings need to be heteroaromatic, the second ring may be a heteroaromatic or an aromatic, saturated, or partially unsatuated carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring. In the case of substituted heteroaryl rings containing at least one nitrogen atom (e.g., pyridine), such substitutions can be those resulting in N-oxide formation. Examples of heteroaryl include, but are not limited to, furanyl, thienyl (or thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-tetrahydroquinolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]-pyrimidinyl, 5,6-dihydropyrrolo[1,2-b]pyrazolyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, thieno[2,3-b]pyrrolyl, furopyridine and thienopyridine.

Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl (i.e.,

imidazo(2,1-b)(1,3)thiazole, (i.e.,

and benzo-1,3-dioxolyl (i.e.,

In certain contexts herein,

is alternatively referred to as phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.

Non-limiting examples of substituted heteroaryls include: isoindolinone, isoindolin-1-one, 2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-4(5H)-one, 2,3,4,5-tetrahydrobenzo[d]isothiazole 1,1-dioxide, and 2,3,4,5-tetrahydrobenzo[b]thiophene 1,1-dioxide.

“Hydroxyalkyl” refers to an alkyl group as described above in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Examples include CH₂OH, CH₂CHOH and CHOHCH₃.

“Alkylene,” “alkenylene,” “alkynylene,” “cycloalkylene,” “arylene,” “heteroarylene,” and “heterocyclylene” refer to a divalent radical obtained by the removal of one hydrogen atom from an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl group, respectively, each of which is as defined above.

Unless expressly stated to the contrary, an “unsaturated” ring is a partially or fully unsaturated ring. For example, an “unsaturated monocyclic C₆ carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.

Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.

When any variable occurs more than one time in any constituent or in any formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term “sulfamoyl” is a suffix to denote radicals derived from sulfamide such as —SO₂NH₂, —SO₂NHR and —SO₂N(RR¹).

The term “sulfonimidoyl” is a suffix to denote the radical

where R is C₍₁₋₁₀₎ alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl and the like, such as for example methyl, ethyl, isopropy and propyl.

The term “substituted” (e.g., as in “aryl which is optionally substituted with one or more substituents . . . ”) includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur (S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

When any variable (e.g., R², R³, etc.) occurs more than one time in any substituent or in Formula I its definition in each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent is equivalent to

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R¹, R², R³, etc., are to be chosen in conformity with well-known principles of chemical structure connectivity.

Lines drawn into the ring systems from substituents indicate that the indicated bond can be attached to any of the substitutable ring atoms. If the ring system is polycyclic, it is intended that the bond be attached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results. The phrase “optionally substituted with one or more substituents” should be taken to be equivalent to the phrase “optionally substituted with at least one substituent” and in such cases one embodiment will have from zero to three substituents.

Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters “CH₃”, e.g. “—CH₃” or using a straight line representing the presence of the methyl group, e.g. “-”, i.e.,

and

have equivalent meanings.

For variable definitions containing terms having repeated terms, e.g., (CR^(i)R^(j))_(r), where r is the integer 2, R^(i) is a defined variable, and R^(j) is a defined variable, the value of R^(i) may differ in each instance in which it occurs, and the value of R^(j) may differ in each instance in which it occurs. For example, if R^(i) and R^(j) are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CR^(i)R^(j))₂ can be

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The term “treatment” or “treating” includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.

The term “composition”, as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, and pharmaceutically acceptable excipients.

The term “optionally substituted” means “unsubstituted or substituted,” and therefore, the generic structural formulas described herein encompasses compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent.

Each variable is independently defined each time it occurs within the generic structural formula definitions. For example, when there is more than one substituent for aryl/heteroaryl, each substituent is independently selected at each occurrence, and each substituent can be the same or different from the other(s). As another example, for the group —(CR³R³)₂—, each occurrence of the two R³ groups may be the same or different. As used herein, unless explicitly stated to the contrary, each reference to a specific compound of the present invention or a generic formula of compounds of the present invention is intended to include the compound(s) as well as pharmaceutically acceptable salts thereof.

In one embodiment of the invention, A is selected from phenyl, methyl, ethyl, pyridinyl, cyclobutyl, cyclopropyl, cyclopropylmethyl, dihydroisoindolyl, dihydrobenzisothiazolyl, dihydroindenyl, isoindolyl, dihydro[b]thiophenyl, 2,3-dihydrobenzo[d]isothiazole-1,1-dioxide 1-oxo-2,3-dihydro-1H-indene and 1,1-dioxido-2,3-dihydrobenzo[b]thiophene.

In one embodiment of the invention, A is selected from: phenyl, methyl, ethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, isoindolinyl, benzo[d]thiazolyl,

2,3-dihydro-1H-indenyl, quinolinyl, pyridinyl, and indolinyl.

In a variant of this embodiment, A is selected from: methyl, ethyl, cyclopropylmethyl, cyclopropyl, and cyclobutyl,

In another variant, A is selected from isoindolinyl, benzo[d]thiazolyl,

2,3-dihydro-1H-indenyl, quinolinyl, pyridinyl, and indolinyl.

In an embodiment of the invention, R² and R³ are each independently selected from hydrogen, methyl, ethyl, propyl and hydroxyl. In a variant of this embodiment, R² and R³ are each a hydrogen.

In another embodiment, R² and R³ join together with the carbon they are attached to form a 3 to 6 membered ring.

In one embodiment of the invention,

of formula I, where p is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; and two R4 together with the ring atom to which each is attached optionally may form a saturated ring, is selected from: piperidinyl, azetidinyl, tetrahydropyranyl, tetrahydro-2H-pyranyl, cyclohexyl, cyclopentyl, tetrahydrofuranyl, and 1,4-dioxaspiro[4.5]decanyl

In another embodiment,

of formula I, where p is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4 is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, cyclopentyl, tetrahydrofuranyl, and azetidinyl.

In one embodiment of the invention, n is 0, 1, 2, 3, or 4. In one embodiment of the invention, n is 0, 1, 2, or 3. In a variant of this embodiment, n is 0, 1, or 2.

In one embodiment of the invention, m is 0, 1, 2, 3 or 4. In one embodiment of the invention, m is 0, 1, 2, or 3. In a variant of this embodiment, m is 0, 1, or 2.

In one embodiment of the invention, p is 1, 2, 3 or 4.

In one embodiment of the invention, p is 0, 1, 2, or 3. In a variant of this embodiment, p is 1, 2, or 3.

In one embodiment of the invention, R⁴ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, C₁₋₁₀ alkylamino(carbonyl)₀₋₁C₀₋₁₀alkyl, (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ amino C₀₋₁₀ alkyl, (C₁₋₁₀)heteroalkylamino(carbonyl)₀₋₁C₀₋₁₀alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, C₀₋₁₀ alkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfonyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₁₋₂amino, —CO₂(C₀₋₁₀ alkyl), —SO₂CF₃, —SO₂CF₂H, —SO₂CH₂CF₃, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl, wherein R⁴ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents, and two R⁴ together with the ring atom to which each is attached optionally may form a saturated ring.

In a variant of this embodiment, R⁴ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, C₁₋₁₀ alkylamino(carbonyl)₀₋₁C₀₋₁₀alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, C₀₋₁₀ alkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl, (C₀₋₁₀ alkyl) 1-2amino, —SO₂CH₂CF₃, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, and C₁₋₆haloalkyl, wherein R⁴ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents, and two R⁴ together with the ring atom to which each is attached optionally may form a saturated ring.

In a variant of this embodiment, R⁴ is selected from tert-butylcarbonyl, methoxycarbonyl, methylcarbonyl, cyclopropylmethyl, cyclopropylmethylcarbonyl, cyclopropylethylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyloxycarbonyl, isopropyloxycarbonyl, phenylmethyl, phenylpropyl, phenylmethylcarbonyl, phenylethylcarbonyl, phenyloxycarbonyl, phenylcarbonyl, oxazolylmethyl, 1,3-oxazolylmethyl, indolylmethyl, 1-phenylethyl, pyridinylmethyl, cyclohexylcarbonyl, fluoro, 2,2,2-trifluoroethyl, ethyl, 2-hydoxyethyl, neopentylcarbonyl, neopentyloxycarbonyl, ethylcarbonyl, ethyloxycarbonyl, methoxymethylcarbonyl (methylamino)methylcarbonyl, 2,3-dihydro-1H-indenylcarbonyl, pyrrolidinylmethylcarbonyl, tetrahydro-2H-pyranylcarbonyl, tetrahydro-2H-thiopyranyloxycarbonyl, tetrahydro-2H-pyranyloxycarbonyl, 1-(pyridinyl)ethyloxycarbonyl, adamantylcarbonyl, tetrahydrofuranyloxycarbonyl, trifluoroethylsulfonyl, dimethylamino, tert-butyloxycarbonyl, methyl, tert-butylaminocarbonyl, aminocarbonyl, azetidinyl, cyclohexylamino, oxo, hydroxy, methylaminocarbonyl, cyclopropylsulfonyl, methoxy, phenylamino, pyridinyl, hydroxyisopropyl, hydroxyeth-2-yl, trifluoromethyl, 2-(methylthio)eth-2-ylcarbonyl, methylsulfonyl, ethylcarbonyl, methylamino, isopropyloxycarbonyl, and hydroxyisopropyl; wherein R⁴ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents, and wherein two R⁴ together with the ring atom to which each is attached optionally may form a saturated ring.

In one embodiment, R⁵ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁ C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkylaminocarbonylC₀₋₁₀alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁aminoC₀₋₁₀ alkyl, —SF₅, C₀₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl, C₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl, heteroarylC₀₋₁₀ alkylsulfamoyl, C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, arylC₀₋₁₀ alkylsulfamoyl, (C₁₋₁₀ alkyl)₁₋₂amino, —SO₂CF₃, —SO₂CF₂H, —SO₂CH₂CF₃, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; wherein R⁵ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents.

In another embodiment, R⁵ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁ C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁ C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkylaminocarbonylC₀₋₁₀alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, (C₁₋₁₀)heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, —SF₅, C₀₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfonyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl, C₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl, heteroarylC₀₋₁₀ alkylsulfamoyl, C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, arylC₀₋₁₀ alkylsulfamoyl, (C₁₋₁₀ alkyl)₁₋₂amino, —SO₂CF₃, —SO₂CF₂H, —SO₂CH₂CF₃, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; and wherein R⁵ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents.

In one embodiment, wherein R⁵ is selected from: oxo, trifluoromethyl, methoxycarbonyl, fluoro, dimethylsulfamoyl, hydroxyethyl, sulfamoyl, trifluoroethyl, methylsulfonyl, methyl, pentafluorosulfanyl, 2,2,2-trifluoroethyl, tert-butyl, (trifluoromethyl)sulfonyl, methylamino, tert-butylsulfamoyl, isopropylsulfonyl, tert-butylsulfamoyl, pyrazolylmethyl, triazolylmethyl, 1,2,3-triazolylmethyl, isobutyl, cyclopropylmethyl, ethyl, cyclopentylmethyl, isopropylsulfamoyl, benzylsulfamoyl, (cyclopropylmethyl)sulfamoyl, (methoxyethyl)sulfamoyl, cyclohexylsulfamoyl, piperidinylsulfonyl, morpholinosulfonyl, difluoromethylsulfonyl, chloro, and methoxy; wherein R⁵ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents.

In another embodiment R⁵ is selected from: methoxycarbonyl, tert-butylsulfonyl, tert-butylsulfamoyl, tert-butyl(methyl)sulfamoyl, tert-butyl(ethyl)sulfamoyl, pentafluorosulfanyl, methoxy, dimethyamino, oxo, amino, fluoro, isobutyl, isopropyl, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, tert-butyloxycarbonyl(1-methyl)ethyl, diethylsulfamoyl, ethylsulfamoyl, pyrrolidinylsulfonyl, methyl, tert-butylaminomethyl, methylaminocarbonyl, methylaminomethyl, ethyl, (1-hydroxy)ethyl, piperidinylsulfonyl, piperidinyl, thiomorpholinylcarbonyl, thiazolidinylcarbonyl, thiomorpholinylmethyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, ethylaminocarbonyl, morpholinylcarbonyl, tert-butyl, cyclopentylmethyl, cyclohexyl, cyclohexylsulfonyl, cyclohexylsulfamoyl, cyclopentyl, cyclopentylsulfonyl, benzyl, hydroxymethyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octane-3carbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, ethoxycarbonyl(dimethyleth-2-yl), hydroxy, trifluoromethyl, azetidinylsulfonyl, cyclopropylsulfonyl, cyclopropyl, chloro, ethylaminomethyl, pyrrolidinylmethyl, 1-pyrrolidin-1-ylethyl, cyclopropylmethyl, pyrazolylmethyl, morpholinylsulfonyl, isopropylaminomethyl, pyrazolyl, pyrrolidinyl, piperadinyl, methylsulfonyl, isopropylsulfonyl, isopropylsulfamoyl, methylsulfamoyl, benzylsulfamoyl, cyclopropylmethyl, cyclobutyl, tert-butylsulfonyl, tert-butyloxycarbonyl, tert-butyloxycarbonylmethyl, methoxymethyl, 2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl, methoxyeth-2-yl, triazolylmethyl, 1,2,3-triazolylmethyl, aminomethyl, ethylaminomethyl, aminocarbonyl, morpholinyl, isopropyl, isopropyl(methy)sulfamoyl, sulfonyl, cyano, 2,2,2-trifluoroethyl, ethylaminocarbonyl, tert-butylaminomethyl, isopropyloxycarbonyl(dimethyleth-2-yl), 1,1,1-trifluoro-3,3-dimethylbut-2-yl, (1,1,2-trimethylpropyl)sulfonyl, (1,1-dimethylpropyl)sulfonyl, isopropylsulfonimidoyl methylsulfonyl, ethylcarbonyl, 2,3-dihydro-1H-indenyl, ethylmethylsulfamoyl, neopentyl, methylaminomethyl dimethylamino, 2-(isopropylamino)propan-2-yl, 2,2-dimethylpropyl, hydroxymethyl, hydroxyeth-2-yl, tert-butyloxycarbonyl(2-methylprop-2-yl), methoxy, ethylaminocarbonyl, methylaminocarbonyl, and methoxymethyl; and wherein R⁵ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents.

In one embodiment, R⁶ is independently selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy, C₀₋₁₀alkylsulfonyl, —CO₂(C₀₋₁₀ alkyl), —(C₀₋₁₀ alkyl)CO₂H, oxo (═O), —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂CF₃, —SO₂CF₂H, amino, (C₀₋₁₀ alkyl)₁₋₂ amino, hydroxy, (C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, and C₁₋₆haloalkyl.

In one embodiment, R⁶ is independently selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, oxo (═O), C₀₋₁₀alkylsulfonyl, amino, hydroxy, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, and C₁₋₆haloalkyl, wherein R⁶ is optionally substituted with 1, 2, or 3 R⁷ substituents

In another embodiment, R⁶ is independently selected from: trifluoromethyl, 2,2,2-trifluroethyl, amino, methyl, fluoro, methoxy, tert-butyl, ethyl, tert-butyloxycarbonyl(1-methyl)ethyl, ethoxycarbonyl, tert-butyloxycarbonylmethyl, phenyl, trifluoroethyl, cyclopropyl, oxo, tert-butyloxycarbonyl, isopropyl, cyano, isopropyloxy, isoxazolyl, pyrrolidinyl, chloro, methylthio, methylsulfonyl, iodine, and bromine; wherein R⁶ is optionally substituted with 1, 2, or 3 R⁷ substituents.

In one embodiment, R⁷ selected from hydrogen, hydroxy, (C₁₋₆)alkyl, halogen, trifluoromethyl, trifluoroethyl, C₁₋₁₀ alkylsulfonyl, oxo (O═), —SO₂CF₃, —SO₂CF₂H, and NH₂.

In a variant of this embodiment R⁷ selected from hydrogen, and oxo (O═).

In one embodiment, the section of formula I,

is selected from:

wherein R² is hydrogen; Q is 0, 1, 2 or 3; R^(4a) is OH, C₍₁₋₄₎ alkyl, oxo, or halogen; p_(b) is independently 0, 1, 2, 3, or 4; and Z is 0, 1, or 2, provided that the sum of Q and Z is less than or equal to 4; R⁴ is selected from tert-butylcarbonyl, methoxycarbonyl, methylcarbonyl, cyclopropylmethyl, cyclopropylmethylcarbonyl, cyclopropylethylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyloxycarbonyl, isopropyloxycarbonyl, phenylmethyl, phenylpropyl, phenylmethylcarbonyl, phenylethylcarbonyl, phenyloxycarbonyl, phenylcarbonyl, oxazolylmethyl, 1,3-oxazolylmethyl, indolylmethyl, 1-phenylethyl, pyridinylmethyl, cyclohexylcarbonyl, fluoro, 2,2,2-trifluoroethyl, ethyl, 2-hydoxyethyl, neopentylcarbonyl, neopentyloxycarbonyl, ethylcarbonyl, ethyloxycarbonyl, methoxymethylcarbonyl (methylamino)methylcarbonyl, 2,3-dihydro-1H-indenylcarbonyl, pyrrolidinylmethylcarbonyl, tetrahydro-2H-pyranylcarbonyl, tetrahydro-2H-thiopyranyloxycarbonyl, tetrahydro-2H-pyranyloxycarbonyl, 1-(pyridinyl)ethyloxycarbonyl, adamantylcarbonyl, tetrahydrofuranyloxycarbonyl, trifluoroethylsulfonyl, dimethylamino, tert-butyloxycarbonyl, methyl, tert-butylaminocarbonyl, aminocarbonyl, azetidinyl, cyclohexylamino, oxo, hydroxy, methylaminocarbonyl, cyclopropylsulfonyl, methoxy, phenylamino, pyridinyl, carbonyl, hydroxyisopropyl, hydroxyeth-2-yl, trifluoromethyl, 2-(methylthio)eth-2-ylcarbonyl, methylsulfonyl, ethylcarbonyl, methylamino, isopropyloxycarbonyl, and hydroxyisopropyl; wherein R⁴ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents and R⁶ is selected from from hydrogen and oxo. In variant of this embodiment, Q is 0, and R⁶ is oxo.

In another embodiment of the invention, the portion of formula I,

is selected from:

and t is 0, 1, 2 or 3; m is 0, 1, or 2; and R^(5a) is selected from halogen, methyl, ethyl, oxo, C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, and (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl; provided that the sum oft plus m is less than or equal to 4. In a variant of this embodiment, R^(5a) is selected from halogen, methyl, ethyl, oxo, and heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl and R⁵ is selected from: methoxycarbonyl, tert-butylsulfonyl, tert-butylsulfamoyl, tert-butyl(methyl)sulfamoyl, tert-butyl(ethyl)sulfamoyl, pentafluorosulfanyl, methoxy, dimethyamino, oxo, amino, fluoro, isobutyl, isopropyl, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, tert-butyloxycarbonyl(1-methyl)ethyl, diethylsulfamoyl, ethylsulfamoyl, pyrrolidinylsulfonyl, methyl, tert-butylaminomethyl, methylaminocarbonyl, methylaminomethyl, ethyl, (1-hydroxy)ethyl, piperidinylsulfonyl, piperidinyl, thiomorpholinylcarbonyl, thiazolidinylcarbonyl, thiomorpholinylmethyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, ethylaminocarbonyl, morpholinylcarbonyl, tert-butyl, cyclopentylmethyl, cyclohexyl, cyclohexylsulfonyl, cyclohexylsulfamoyl, cyclopentyl, cyclopentylsulfonyl, benzyl, hydroxymethyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octane-3carbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, ethoxycarbonyl(dimethyleth-2-yl), hydroxy, trifluoromethyl, azetidinylsulfonyl, cyclopropylsulfonyl, cyclopropyl, chloro, ethylaminomethyl, pyrrolidinylmethyl, 1-pyrrolidin-1-ylethyl, cyclopropylmethyl, pyrazolylmethyl, morpholinylsulfonyl, isopropylaminomethyl, pyrazolyl, pyrrolidinyl, piperadinyl, methylsulfonyl, isopropylsulfonyl, isopropylsulfamoyl, methylsulfamoyl, benzylsulfamoyl, cyclopropylmethyl, cyclobutyl, tert-butylsulfonyl, tert-butyloxycarbonyl, tert-butyloxycarbonylmethyl, methoxymethyl, 2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl, methoxyeth-2-yl, triazolylmethyl, 1,2,3-triazolylmethyl, aminomethyl, ethylaminomethyl, aminocarbonyl, morpholinyl, isopropyl, isopropyl(methy)sulfamoyl, sulfonyl, cyano, 2,2,2-trifluoroethyl, ethylaminocarbonyl, tert-butylaminomethyl, isopropyloxycarbonyl(dimethyleth-2-yl), 1,1,1-trifluoro-3,3-dimethylbut-2-yl, (1,1,2-trimethylpropyl)sulfonyl, (1,1-dimethylpropyl)sulfonyl, isopropylsulfonimidoyl methylsulfonyl, ethylcarbonyl, 2,3-dihydro-1H-indenyl, ethylmethylsulfamoyl, neopentyl, methylaminomethyl dimethylamino, 2-(isopropylamino)propan-2-yl, 2,2-dimethylpropyl, hydroxymethyl, hydroxyeth-2-yl, tert-butyloxycarbonyl(2-methylprop-2-yl), methoxy, ethylaminocarbonyl, methylaminocarbonyl, and methoxymethyl; and wherein R⁵ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents.

In one embodiment of the invention provides compounds of Formula I or pharmaceutically acceptable salts, or stereoisomers thereof:

-   A is selected from aryl, heteroaryl, cycloalkylC₍₀₋₁₀₎alkyl,     C₁₋₆alkyl; -   R² and R³ are each independently selected from hydrogen, C₁₋₄alkyl     and hydroxyl, wherein R² and R³ may optionally, join together with     the carbon they are attached to form a 3 to 6 membered ring; -   X₁ is C; -   X₂, X₃, and X₄ are each independently selected from O, N, S, and C     and provided that the formed ring system contains 0, 1, 2, or 3     atoms selected from O, N and S; -   n is 0, 1, 2, 3 or 4; -   m is 0, 1, 2, 3 or 4; -   p is 0, 1, 2, 3, or 4; -   R⁴ is selected from:     -   halogen,     -   oxo (═O),     -   C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀         alkyl,     -   C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl,     -   C₀₋₁₀ alkylamino(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ amino C₀₋₁₀ alkyl,     -   (C₁₋₁₀)heteroalkylamino(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   sulfonyl,     -   C₁₋₁₀ alkylsulfonyl,     -   C₁₋₁₀ heteroalkylsulfonyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl,     -   heteroarylC₀₋₁₀ alkylsulfonyl,     -   arylC₀₋₁₀ alkylsulfonyl,     -   —SO₂NH₂,     -   —SO₂NH(C₁₋₆alkyl),     -   —SO₂N(C₁₋₆alkyl)₂,     -   C₁₋₁₀ alkylsulfamoyl,     -   C₁₋₁₀ heteroalkylsulfamoyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl,     -   heteroarylC₀₋₁₀ alkylsulfamoyl,     -   arylC₀₋₁₀ alkylsulfamoyl,     -   (C₀₋₁₀ alkyl)₁₋₂ amino,     -   —CO₂(C₀₋₁₀ alkyl),     -   —(C₀₋₁₀ alkyl)CO₂H,     -   —SO₂CF₃,     -   —SO₂CF₂H,     -   C₁₋₁₀ alkylsulfinyl,     -   C₁₋₄acylaminoC₀₋₁₀ alkyl,     -   hydroxy,     -   —(C₁₋₁₀ alkyl)OH,     -   —C₀₋₁₀ alkylalkoxy,     -   cyano,     -   (C₁₋₆alkyl)cyano, and     -   C₁₋₆haloalkyl,

wherein two R4 together with the ring atom to which each is attached optionally may form a saturated ring;

-   R⁵ is selected from:     -   halogen,     -   oxo (═O),     -   C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀         alkyl,     -   C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl,     -   (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl,     -   —SF₅,     -   C₁₋₁₀ alkylsulfonyl,     -   C₁₋₁₀ heteroalkylsulfonyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl,     -   heteroarylC₀₋₁₀ alkylsulfonyl,     -   arylC₀₋₁₀ alkylsulfonyl,     -   C₀₋₁₀ alkylsulfamoyl,     -   C₁₋₁₀ heteroalkylsulfamoyl,     -   (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl,     -   (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl,     -   heteroarylC₀₋₁₀ alkylsulfamoyl,     -   —SO₂NH₂,     -   —SO₂NH(C₁₋₆alkyl),     -   —SO₂N(C₁₋₆alkyl)₂,     -   arylC₀₋₁₀ alkylsulfamoyl,     -   (C₀₋₁₀ alkyl)₁₋₂ amino,     -   —CO₂(C₀₋₁₀ alkyl),     -   —(C₀₋₁₀ alkyl)CO₂H,     -   —SO₂CF₃,     -   —SO₂CF₂H,     -   C₁₋₁₀ alkylsulfinyl,     -   C₁₋₄acylaminoC₀₋₁₀ alkyl,     -   hydroxy,     -   —(C₁₋₁₀ alkyl)OH,     -   C₀₋₁₀ alkylalkoxy,     -   cyano,     -   (C₁₋₆alkyl)cyano, and     -   C₁₋₆haloalkyl; and         wherein R⁴ and R⁵ are each optionally substituted with 1, 2, 3,         or 4 R⁶ substituents and R⁶ is independently selected from:     -   halogen,     -   C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀         alkyl,     -   C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,     -   C₂₋₁₀ alkenyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   aryl C₀₋₁₀ alkyl (carbonyl)₀₋₁oxyC₀₋₁₀ alkyl,     -   (C₃₋₁₂)cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   heteroarylC₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl,     -   ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy,     -   aryl (C₀₋₁₀)alkylaminocarbonyloxy,     -   —CO₂(C₀₋₁₀ alkyl),     -   —(C₀₋₁₀ alkyl)CO₂H,     -   oxo (═O),     -   C₁₋₁₀ alkylsulfonyl,     -   C₁₋₁₀ heteroalkylsulfonyl,     -   (C₃₋₁₂) cycloalkylsulfonyl,     -   (C₃₋₁₂) cycloheteroalkylsulfonyl,     -   heteroarylsulfonyl,     -   arylsulfonyl,     -   aminosulfonyl,     -   —SO₂NH₂,     -   —SO₂NH(C₁₋₆alkyl),     -   —SO₂N(C₁₋₆alkyl)₂,     -   —SO₂CF₃,     -   —SO₂CF₂H,     -   C₁₋₁₀ alkylsulfinyl,     -   amino,     -   (C₀₋₁₀ alkyl)₁₋₂ amino,     -   -(oxy)₀₋₁(carbonyl)₀₋₁N(C₀₋₁₀ alkyl)₁₋₂     -   C₁₋₄acylaminoC₀₋₁₀ alkyl,     -   hydroxy,     -   (C₁₋₁₀ alkyl)OH,     -   C₁₋₁₀ alkoxy,     -   (C₁₋₁₀ alkyl)cyano,     -   cyano, and     -   C₁₋₆haloalkyl; and     -   R⁶ is optionally substituted with 1, 2, or 3 substituents         selected from hydrogen, hydroxy, (C₁₋₆)alkyl, (C₁₋₆)alkoxy,         (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆         alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl,         trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, oxo         (O═), aminosulfonyl, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —C₁₋₁₀         alkylsulfinyl, —O₍₀₋₁₎(C₁₋₁₀)halo, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl),         —SO₂N(C₁₋₆alkyl)₂, alkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I, either as single species or mixtures thereof.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.

Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the examples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as “stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. When bonds to the chiral carbon are depicted as straight lines in the formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. For example, Formula I shows the structure of the class of compounds without specific stereochemistry. When the compounds of the present invention contain one chiral center, the term “stereoisomer” includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as racemic mixtures.

The compounds of formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, if a compound of formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

In the present application when a particular stereomeric compound is named using an “and” in the stereomeric designation, for example, tert-butyl (3R,4S and 3S,4R)-4-(cyanomethyl)-3-methyl-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate, the “and” indicates a racemic mixture of the enantiomers. That is, the individual enantiomers were not individually isolated.

When the stereomeric nomenclature includes “or”, for example, tert-butyl 4-(cyanomethyl)-4-[4-oxo-3-({4-[(1R or 1S)-2,2,2-trifluoro-1-hydroxyethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate, the “or” indicates that chiral resolution of racemate into individual enantiomers was accomplished but the actual optical activity of the specific enantiomer was not nessissarily determined.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Salt

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, 1-hydroxy-2-naphthoic acid (xinafoate) and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, unless otherwise specified, references to the compound of Formula I subsets thereof, embodiments thereof, as well as specific compounds are meant to also include the pharmaceutically acceptable salts and stereoisomers thereof.

Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such all forms are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water (hydrates) or common organic solvents. Such solvates are encompassed within the scope of this invention.

Labelled Compounds

In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (¹H) and deuterium (²H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.

Utilities

Compound of Formula I or its pharmaceutically acceptable salts and pharmaceutical compositions can be used to treat or prevent a variety of conditions or diseases mediated by Janus kinases, in particular diseases or conditions that can be ameliorated by the inhibition of a Janus kinase such as JAK1, JAK2, JAK3 or TYK2. Such conditions and diseases include, but are not limited to:

(1) arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis; (2) asthma and other obstructive airways diseases, including chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease including emphysema; (3) autoimmune diseases or disorders, including those designated as single organ or single cell-type autoimmune disorders, for example Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which can be B-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis; (4) cancers or tumors, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, including acute myelogenous leukemia and chronic myelogenous leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myelomas including multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, and angiogenic-associated disorders including solid tumors; (5) diabetes, including Type I diabetes and complications from diabetes; (6) eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization; (7) intestinal inflammations, allergies or conditions including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease, coeliac diseases, proctitis, eosinophilic gastroenteritis, and mastocytosis; (8) neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, and platelet aggregation; (9) skin diseases, conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions; (10) allergic reactions including anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, or allergic reaction to insect bites, food, drugs, or pollen; (11) transplant rejection, including pancreas islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, and xeno transplantation.

Accordingly, another aspect of the present invention provides a method for the treatment or prevention of a JAK-mediated disease or disorder comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I. In one embodiment such diseases include asthma and rheumatoid arthritis.

Another aspect of the present invention provides for the use of a compound of Formula I in the manufacture of a medicament for the treatment or prevention of a JAK-mediated disease or disorder.

One aspect of the invention is the use of a compound of Formula I or a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the treatment of a disease or a disorder ameliorated by inhibition of Janus kinases JAK1 and JAK2.

Another aspect of the invention is the use of a compound of Formula I or a pharmaceutically acceptable salt or a stereoisomer thereof and a second active agent in the manufacture of a medicament for the treatment of a disease or a disorder ameliorated by inhibition of Janus kinases JAK1 and JAK2.

Dose Ranges

The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.05 mg to 5 g, of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition. In some cases, the dosage unit forms may contain from about 0.05 to about 3 g of active ingredient. Dosage unit forms will generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, typically 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 400 mg.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceutical compositions comprising a compound of Formula I with a pharmaceutically acceptable carrier. For the treatment of any of the prostanoid mediated diseases compounds of Formula I may be administered orally, by inhalation spray, topically, parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and U.S. Pat. No. 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders. For compositions suitable and/or adapted for inhaled administration, it is preferred that the active substance is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronization.

In one embodiment the medicinal preparation is adapted for use with a pressurized metered dose inhaler (pMDI) which releases a metered dose of medicine upon each actuation. The formulation for pMDIs can be in the form of solutions or suspensions in halogenated hydrocarbon propellants. The type of propellant being used in pMDIs is being shifted to hydrofluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs). In particular, 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) are used in several currently marketed pharmaceutical inhalation products. The composition may include other pharmaceutically acceptable excipients for inhalation use such as ethanol, oleic acid, polyvinylpyrrolidone and the like.

Pressurized MDIs typically have two components. Firstly, there is a canister component in which the drug particles are stored under pressure in a suspension or solution form. Secondly, there is a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well. The canister component typically includes a valve outlet from which the contents of the canister can be discharged. Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valve outlet and causing the medication particles to be conveyed from the valve outlet through the receptacle component and discharged from an outlet of the receptacle. Upon discharge from the canister, the medication particles are “atomized”, forming an aerosol. It is intended that the patient coordinate the discharge of aerosolized medication with his or her inhalation, so that the medication particles are entrained in the patient's aspiratory flow and conveyed to the lungs. Typically, pMDIs use propellants to pressurize the contents of the canister and to propel the medication particles out of the outlet of the receptacle component. In pMDIs, the formulation is provided in a liquid or suspension form, and resides within the container along with the propellant. The propellant can take a variety of forms. For example, the propellant can comprise a compressed gas or liquefied gas.

In another embodiment the medicinal preparation is adapted for use with a dry powder inhaler (DPI). The inhalation composition suitable for use in DPIs typically comprises particles of the active ingredient and particles of a pharmaceutically acceptable carrier. The particle size of the active material may vary from about 0.1 μm to about 10 μm; however, for effective delivery to the distal lung, at least 95 percent of the active agent particles are 5 μm or smaller. Each of the active agent can be present in a concentration of 0.01-99%. Typically however, each of the active agents is present in a concentration of about 0.05 to 50%, more typically about 0.2-20% of the total weight of the composition.

As noted above, in addition to the active ingredients, the inhalable powder preferably includes pharmaceutically acceptable carrier, which may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation. Advantageously, the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols. Preferably, the carrier particles are particles of dextrose or lactose, especially lactose. In embodiments of the present invention which utilize conventional dry powder inhalers, such as the Handihaler, Rotohaler, Diskhaler, Twisthaler and Turbohaler, the particle size of the carrier particles may range from about 10 microns to about 1000 microns. In certain of these embodiments, the particle size of the carrier particles may range from about 20 microns to about 120 microns. In certain other embodiments, the size of at least 90% by weight of the carrier particles is less than 1000 microns and preferably lies between 60 microns and 1000 microns. The relatively large size of these carrier particles gives good flow and entrainment characteristics. Where present, the amount of carrier particles will generally be up to 95%, for example, up to 90%, advantageously up to 80% and preferably up to 50% by weight based on the total weight of the powder. The amount of any fine excipient material, if present, may be up to 50% and advantageously up to 30%, especially up to 20%, by weight, based on the total weight of the powder. The powder may optionally contain a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.

Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

Combinations with Other Drugs

For the treatment and prevention of JAK mediated diseases, compound of Formula I may be co-administered with other therapeutic agents. Thus in another aspect the present invention provides pharmaceutical compositions for treating JAK mediated diseases comprising a therapeutically effective amount of a compound of Formula I and one or more other therapeutic agents. In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of Formula I may be combined with agents such as: (1) TNF-α inhibitors such as Remicade® and Enbrel®); (2) non-selective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); (3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib); (4) other agents for treatment of rheumatoid arthritis including low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as zileuton; (6) LTD4 receptor antagonist such as zafirlukast, montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast; (8) antihistaminic H1 receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine; (9) α1- and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride; (10) anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropium bromide, aclindinium bromide, glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol, or methylxanthanines including theophylline and aminophylline, sodium cromoglycate; (12) insulin-like growth factor type I (IGF-1) mimetic; (13) inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate.

Schemes and Examples

The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.

AD adamantyl ACN, MeCN acetonitrile BAST bis(2-methoxyethyl)aminosulfur trifluoride t-Bu XPhos 2-di tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl Chiral SFC chiral super critical fluid chromatography CO₂ carbon dioxide Cs₂CO₃ cesium carbonate dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DEA diethylamine DIPEA N,N-diisopropylethylamine DMEA dimethylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DSC N,N-disuccinimidyl carbonate EDC 3-(ethyliminomethyleneamino)-N,N-dimethyl- propan-1-amine EtOAc ethyl acetate ESI electro spray ionization GCMS gas chromatography/mass spectrometry HATU O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate HCl hydrogen chloride HOBt 1-hydroxybenzotriazole HPLC high pressure liquid chromatography IPA 2-propanol LDA lithium diisopropylamide m-CPBA meta-chloroperoxybenzoic acid LR low resolution LRMS low resolution mass spectrometry MeI iodomethane Me-THF 2-methyltetrahydrofuran Me₄-t-Bu-X-Phos di-tert-butyl[3,4,5,6-tetramethyl-2′,4′,6′-tri(propan-2- yl)biphenyl-2-yl]phosphane MgSO₄ magnesium sulfate MP-(OAc)₃BH solid supported (macro porous) triacetoxyborohydride MPLC medium pressure liquid chromatography NaH sodium hydride Na₂SO₄ sodium sulfate NaBH₄ sodium borohydride NaHCO₃ sodium bicarbonate NaOMe sodium methoxide NMO 4-methylmorpholine N-oxide Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) POCl₃ phosphorus (V) oxychloride PS-CDI polystyrene bound carbonyldiimidazole PyBOP (7-azabenzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride SFC Supercritical fluid chromatography SiliaCat ® DPP-Pd silica bound diphenylphosphine palladium (II) TBAF tetra-n-butylammonium fluoride TBS-Cl tert-butyldimethylsilyl chloride t-BuOH tert-butanol t-Bu Xphos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TPAP tetra-n-propylammonium perruthenate (VII) Tr retention time X-Phos 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl HCOOH formic acid Kt-OBu potassium tert-butoxide Na₂S₂O₅ sodium metabisulfite NMR nuclear magnetic resonance TLC thin layer chromatography (EtO)₂P(O)CH₂CN diethyl (cyanomethyl)phosphonate MsCl methanesulfonyl chloride TsOH p-toluenesulfonic acid KCN potassium cyanide Si-DMT silica supported dimercaptotriazine TMS trimethylsilane CF₃TMS (trifluoromethyl)trimethylsilane

Alkyl Group Abbreviations

Me methyl Et ethyl n-Pr normal propyl i-Pr isopropyl n-Bu normal butyl i-Bu isobutyl s-Bu secondary butyl t-Bu tertiary butyl c-Pr cyclopropyl c-Bu cyclobutyl c-Pen cyclopentyl c-Hex cyclohexyl

Methods of Synthesis

The compounds of the present invention can be prepared according to the following general schemes using appropriate materials, and are further exemplified by the subsequent specific examples. The compounds illustrated in the examples are not to be construed as forming the only genus that is considered as the invention. The illustrative Examples below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions of the instant invention herein above.

Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:

-   All reactions were stirred (mechanically, stir bar/stir plate, or     shaken) and conducted under an inert atmosphere of nitrogen or argon     unless specifically stated otherwise. -   All starting materials used to prepare the intermediates and final     compounds described herein were obtained from commercial vendors,     and were used as is upon receipt. -   All temperatures are degrees Celsius (° C.) unless otherwise noted. -   Ambient temperature is 15-25° C. -   Most compounds were purified by reverse-phase preparative HPLC, MPLC     on silica gel, SFC, recrystallization and/or swish (suspension in a     solvent followed by filtration of the solid). -   The course of the reactions was followed by thin layer     chromatography (TLC) and/or LCMS and/or NMR and reaction times are     given for illustration only. -   All end products were analyzed by NMR and LCMS. -   Intermediates were analyzed by NMR and/or TLC and/or LCMS.

Method 1

General procedures to prepare intermediates of the instant invention are described in Scheme 1. Optionally substituted alkyl aldehydes or ketones I are condensed with diethyl (cyanomethyl)phosphonate in the presence of a suitable base, such as potassium tert-butoxide, potassium hydroxide, sodium hydride, or triethylamine/LiBr to yield substituted acrylonitriles II used as intermediates in the synthesis of examples of the instant invention.

Method 2

General procedures to prepare intermediates of the instant invention are described in Scheme 2. In Scheme 2, The sum of n+m can be 1, 2, 3, or 4. Optionally substituted carbamate protected heterocyclic ketones III are condensed with diethyl (cyanomethyl)phosphonate or another suitable cyanoalkylphosphonate in the presence of a suitable base, such as potassium tert-butoxide or TEA/LiBr, to yield optionally substituted acrylonitriles IV used as intermediates in the synthesis of examples of the instant invention.

Method 3

General procedures to prepare intermediates of the instant invention are described in Scheme 3. Carbamate protected optionally substituted acrylonitriles IV are deprotected in the presence of a suitable acid, such as TFA or HCl, to form amino intermediates V that are further derivatized to form sulfonamides VI, carbamates VII, N-arylated intermediates VIII, or amides IX. Sulfonamide derivatives VI are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted sulfonyl chlorides in a suitable solvent, such as DCM, using an appropriate base, such as DIPEA. Carbamate derivatives VII are formed by reacting deprotected optionally substituted acrylonitriles with a doubly activated carbonyl equivalent, such as DSC or triphosgene, and optionally substituted alcohols in the presence of a suitable base, such as TEA. Alternatively, carbamate derivatives VII may be prepared via reaction of the amine and an activated carbamoyl moiety such as an alkyl chloroformate in the presence of a suitable base, such as 2,6-lutidine, DIPEA or TEA, in a suitable solvent such as DCM. N-arylated derivatives VIII are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted electronically-deficient aryl halides using an appropriate base, such as TEA, in a solvent, such as DMF or NMP, at or around 120° C. Amide derivatives IX are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted carboxylic acids in the presence of a suitable coupling agent such as EDC, CDI or HATU, in the presence of a suitable base such as TEA or Hunig's base. Alternatively, amide derivatives IX can be prepared in certain instances using an activated acylating reagent such as the acid chloride in place of the carboxylic acid.

Method 4

General procedures to prepare intermediates of the instant invention are described in Scheme 4. Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, n-BuOH or tert-BuOH, at a temperature between 25-110° C. either the unprotected pyrazolopyridone X or protected pyrazolopyridone XI can undergo conjugate addition to optionally substituted acrylonitriles to yield alkylated unprotected pyrazolopyridones XII or protected pyrazolopyridones XIII, an intermediate in the synthesis of examples of the instant invention. Deprotection of XIII to the free alkylated pyridone XII can then be effected either using a suitable acid, such as TFA, or under hydrogenolysis conditions using Pd on carbon at approximately 1 atmosphere of hydrogen, in a suitable solvent such as EtOAc, EtOH, MeOH, or using combinations of solvents thereof.

Method 5

General procedures to prepare examples of the instant invention are described in Scheme 5. Alkylated 3-amino pyrazolopyrimidines XIII (R₂═H) are cross coupled to aryl and heteroaryl halides XIV using an appropriate catalytic palladium-ligand system, such as Pd₂(dba)₃ or Pd₂(dba)₃.CHCl₃, and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (t-Bu XPhos) or di-tert-butyl[3,4,5,6-tetramethyl-2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (Me₄ ^(t)Bu-XPhos), or 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos). Typical conditions employ 1-2 equivalents of the aryl/heteroaryl halide relative to the pyrazolopyrimidine with 10-25% Pd precatalyst loading, using an approximate Pd:ligand ratio of 1:2 to 1:2.5. Typically, the cross coupling is carried out using either 2-propanol or t-amyl alcohol solvents, and between 1-3.1 equivalents of KOAc or K₃PO₄ base. Reactions were typically carried out between 65-90° C., to yield intermediates XV of the instant invention.

Method 6

General procedures to prepare examples of the instant invention are described in Scheme 6. Carbamate containing deprotected pyrazolopyridones XVII are deprotected in the presence of a suitable acid, such as TFA or HBF₄.OEt₂, to form amino intermediates XVIII that are further derivatized to form sulfonamides IXX, carbamates XX, tertiary amines XXI, N-arylated intermediates XXII, or amides XXIII. Sulfonamide derivatives IXX are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted sulfonyl chlorides in a suitable solvent, such as DCM, using an appropriate base, such as DIPEA or TEA. Carbamate derivatives XX are formed by reacting deprotected optionally substituted acrylonitriles with a doubly activated carbonyl equivalent, such as DSC or triphosgene, and optionally substituted alcohols in the presence of a suitable base, such as DIPEA or TEA. Alternatively, carbamate derivatives XX may be prepared via reaction of the amine and an activated carbamoyl moiety such as an alkyl chloroformate in the presence of a suitable base, such as 2,6-lutidine, DIPEA or TEA, in a suitable solvent such as DCM. Tertiary amine derivatives XXI may be prepared via reaction of the amine an an appropriate carbonyl containing compound, such as an aldehyde or ketone, in the presence of a suitable acid catalyst such as TFA and a suitable reducing agent, such as sodium triacetoxyborohydride. N-arylated derivatives XXII are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted electronically-deficient aryl halides using an appropriate base, such as TEA, in a solvent, such as DMF or NMP, at or around 120° C. Amide derivatives XXIII are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted carboxylic acids in the presence of a suitable coupling agent such as EDC, CDI or HATU, in the presence of a suitable base such as TEA or DIPEA. Alternatively, amide derivatives XXIII can be prepared in certain instances using an activated acylating reagent such as the acid chloride in place of the carboxylic acid.

Method 7

General procedures to prepare examples of the instant invention are described in Scheme 7. Protected pyrazolopyrimidines XV are deprotected in the presence of acid, such as TFA or HCl, to afford the deprotected pyrazolopyridones XVI. Alternatively, in the case of hydrolytically unstable pyridone protecting groups (e.g. PG=Bn), deprotection could be achieved under hydrogenolysis conditions using Pd on Carbon in the presence of hydrogen in a suitable solvent such as EtOAc, EtOH, MeOH, or combinations of solvents thereof.

INTERMEDIATES

The following experimental procedures detail the preparation of chemical materials used in the synthesis of examples of the instant invention. The exemplified procedures are for illustrative purposes only, and are not intended to limit the scope of the instant invention in any way.

Intermediate 1 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine

Step 1: 2-(benzyloxy)-4-methoxynicotinonitrile

To a solution of 2-hydroxy-4-methoxynicotinonitrile (60 g, 0.4 mol) in toluene (0.60 L) was added Ag₂CO₃ (0.14 kg, 0.51 mol) and BnBr (87 g, 0.51 mol) at room temperature. The mixture was stirred at 50° C. for 3 hours. The mixture was filtered and the cake washed with DCM. The filtrate was concentrated in vacuo and petroleum ether (100 mL) was added to the residue and the solid was filtered to give 2-(benzyloxy)-4-methoxynicotinonitrile as a solid. LRMS (ESI) calc'd for C₁₄H₁₃N₂O₂ [M+H]⁺: 241. found 241. ¹H NMR (600 MHz CDCl₃): δ 8.21 (d, J=6.6 Hz, 1H), 7.48 (d, J=7.8 Hz, 2H), 7.38 (m, 2H), 7.32 (m, 1H), 6.58 (d, J=6.0 Hz, 1H), 5.51 (s, 2H), 3.99 (s, 3H).

Step 2: 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine

A suspension of 2-(benzyloxy)-4-methoxynicotinonitrile (100 g, 410 mmol) in hydrazine hydrate (0.20 kg, 4.1 mol) and n-BuOH (600 mL) was heated to reflux overnight. The mixture was concentrated in vacuo and purified by silica chromatography, eluting with 25% ethyl acetate in hexanes. Concentration of the desired fraction in vacuo afforded compound I-1. ¹H NMR (400 MHz CDCl₃) δ 9.97 (s, 1H), 7.75 (d, J=6.4 Hz, 1H), 7.40 (d, J=7.2 Hz, 2H), 7.24-7.33 (m, 3H), 6.69 (d, J=6.4 Hz, 1H), 5.46 (s, 2H), 4.50 (s, 2H).

Intermediate 2 3-amino-1H-pyrazolo[4,3-c]pyridin-4-ol

3-Cyano-2-hydroxy-4-methoxypyridine (1.00 g, 6.66 mmol) was dissolved in hydrazine hydrate (24.8 mL, 260 mmol) in a pressure vessel. The reaction mixture was heated to 140° C. for 21 hours, then cooled to ambient temperature and allowed to stir for an additional 48 hours. The reaction mixture was concentrated to give a solid that was slurried in diethyl ether, filtered, and washed with diethyl ether. The solid was dried under vacuo to give 1-2. LRMS (ESI) calc'd for C₆H₇N₄O [M+H]⁺: 151. found 151.

Intermediate 3 3-(phenylamino)-1H-pyrazolo[4,3-c]pyridin-4(5H)-one

3-Amino-1H-pyrazolo[4,3-c]pyridin-4-ol (50.0 mg, 0.333 mmol), 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (4.0 mg, 8.3 gmol), Pd₂dba₃ (30.5 mg, 0.033 mmol), potassium phosphate tribasic (141 mg, 0.666 mmol), and bromobenzene (26 μL, 0.25 mmol) were suspended in 2-propanol (3.0 mL). The reaction mixture was sparged with argon for 10 minutes, then heated to 75° C. for 2 hours. The reaction mixture was diluted in 3:1 chloroform/isopropanol, washed with water and brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase chromatography, eluting with acetonitrile/water with 0.1% TFA modifier. The fractions containing the desired product were combined and diluted in 3:1 chloroform/isopropanol, washed with aqueous sodium bicarbonate and brine. The combined aqueous layers were back extracted with 3:1 chloroform/isopropanol (×1) and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to give the desired product I-3 as a solid. LRMS (ESI) calc'd for C₁₂H₁₁N₄O [M+H]⁺: 227. found 227.

Intermediate I-4 4-fluorodihydro-2H-pyran-3(4H)-one

Step 1: ((5,6-dihydro-2H-pyran-3-yl)oxy)trimethylsilane

Dihydro-2H-pyran-3(4H)-one (4.00 g, 40.0 mmol) was dissolved in THF (32.0 mL) and chlorotrimethylsilane (12.8 mL, 100 mmol) was added. The reaction was stirred at room temperature for 10 minutes. Triethylamine (15.0 mL, 108 mmol) was then added dropwise under nitrogen. A white precipitate formed and the resulting suspension was heated to 70° C. over the weekend. The reaction mixture was cooled to room temperature and concentrated in vacuo. Pentane (80 mL) was added, the suspension was filtered, and the solid was washed with pentane (40 mL). The filtrate was concentrated in vacuo to give the title compound as a liquid that was used as is in the next step without further purification. ¹H NMR (500 MHz, CDCl₃) δ 4.98-4.92 (m, 1H), 3.88 (m, 2H), 3.69 (t, J=5.5 Hz, 2H), 2.16 (m, 2H), 0.19 (s, 9H).

Step 2: 4-fluorodihydro-2H-pyran-3(4H)-one (I-4)

To a solution of ((5,6-dihydro-2H-pyran-3-yl)oxy)trimethylsilane (5.1 g, 30 mmol) in acetonitrile (75.0 mL) at 0° C., was added Selectfluor® (15.8 g, 44.5 mmol). The reaction was then stirred to room temperature overnight, diluted with ethyl acetate, washed with brine, and the aqueous layer was extracted with ethyl acetate (×2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo to afford a solid. The solid was taken up in DCM, filtered, and concentrated in vacuo to afford I-4 as a liquid that was used without further purification. ¹H NMR (500 MHz, CDCl₃) δ 5.06 (ddd, J=6.9, 11.1, 48.0 Hz, 1H), 4.21 (dd, J=4.5, 14.9 Hz, 1H), 4.11 (dt, J=4.1, 12.7 Hz, 1H), 3.84 (m, 2H), 2.50 (m, 1H), 2.37-2.24 (m, 1H).

Intermediate 5-1 tert-butyl 4-(cyanomethylene)-3-fluoropiperidine-1-carboxylate

To a solution of diethyl (cyanomethyl)phosphonate (67 g, 0.38 mol) in THF (0.70 L) was added TEA (70 g, 0.69 mol) and LiBr (36 g, 0.42 mol) at room temperature. The reaction was stirred at room temperature for 30 minutes before tert-butyl-3-fluoro-4-oxopiperidine-1-carboxylate (75 g, 0.35 mol) was added. The reaction was stirred for another 3 hours, then H₂O (1.0 L) was added, and the mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 10% ethyl acetate in hexanes. Concentration in vacuo of the desired fractions afforded the desired product as a solid, I-5-1. ¹H NMR (600 MHz DMSO-d6): δ 5.88 (s, 1H), 5.27 (m, 0.5H), 5.19 (m, 0.5H), 3.86-3.40 (br m, 4H), 2.65 (m, 1H), 2.51 (m, 1H), 1.45 (s, 9H).

Following analogous procedure as described above for Intermediate 5-1, the following acrylonitrile intermediates shown in Table 1 were prepared:

TABLE 1 Intermediate # Structure Compound Name ¹H NMR/MS 1-5-2

tert-butyl 4- (cyanomethylene)-3- methylpiperidine-1- carboxylate LRMS (ESI) calc'd for C₈H₁₃N₂ [M − Boc + H]⁺: 137, found 137. 1-5-3

2-(4-fluorodihydro-2H- pyran-3(4H)- ylidene)acetonitrile ¹H NMR (500 MHz, CDCl₃) δ 5.66-5.50 (m, 1H), 5.55 (s, 1H), 5.26-5.08 (m, 1H), 4.75 (dd, J = 4.1, 13.6 Hz, 1H), 4.33 (m, 1H), 3.62 (dddd, J = 1.3, 2.6, 10.7, 12.0 Hz, 1H), 2.30-2.14 (m, 1H), 2.12- 1.96 (m, 1H).

Intermediate 6-1 tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate

To a cooled, 0° C. solution of potassium tert-butoxide (263 mL, 263 mmol, 1.0 M in THF) and THF (200 mL), was slowly added diethyl (cyanomethyl)phosphonate (43.7 mL, 276 mmol). The reaction mixture was maintained at 0° V for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0° C. and treated with the dropwise addition of tert-butyl 4-oxopiperidine-1-carboxylate (50.0 g, 251 mmol) in THF (150 mL) over 30 minutes. After addition, the mixture was maintained at 0° C. for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water (800 mL) and extracted with EtOAc (×2). The combined organic extracts were washed with water, brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound as a solid, I-6-1. ¹H NMR (600 MHz, CDCl₃): δ 5.19 (s, 1H), 3.48-3.53 (m, 4H), 2.56 (t, J=5.4 Hz, 2H), 2.33 (t, J=5.4 Hz, 2H), 1.47 (s, 9H).

Following an analogous procedure to that used for Intermediate I-6-1, the following acrylonitrile intermediates in Table 2 were prepared:

TABLE 2 Intermediate # Structure Compound Name ¹H NMR/LRMS 1-6-2

2 (dihydro-2H-pyran-3(4H)- ylidene)acetonitrile LRMS (ESI) calc'd for C₇H₁₀NO [M + H]⁺: 124, found 124. 1-6-3

tert-butyl 3- (cyanomethylidene)azetidine- 1-carboxylate ¹H NMR (600 MHz, CDCl₃): δ 5.38-5.35 (m, 1H), 4.69 (m, 2H), 4.61-4.58 (m, 2H), 1.44 (s, 9H). 1-6-4

2-(1,4-dioxaspiro[4.5]decan-8- ylidene)acetonitrile ¹H NMR (600 MHz, CDCl₃): δ 5.11 (s, 1H), 3.97 (m, 4H), 2.65 (t, J = 7.1 Hz, 2H), 2.42 (t, J = 7.1 Hz, 2H), 1.78 (t, J = 7.1 Hz, 2H), 1.75 (t, J = 7.1 Hz, 2H). 1-6-5

2-cyclopentylideneacetonitrile ¹HNMR (CDCl₃, 500 MHz): δ 5.22 (m, 1H), 2.60-2.56 (m, 2H), 2.45-2.41 (m, 2H), 1.30-1.20 (m, 4H).

Intermediates 7-1 and 7-2 (3R,4S and 3S,4R)-tert-butyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate (I-7-1), and (3S,4S and 3R,4R)-tert-butyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate (I-7-2)

To a solution of tert-butyl 4-(cyanomethylene)-3-fluoropiperidine-1-carboxylate (50 g, 208 mmol) and 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (25 g, 104 mmol) in CH₃CN (200 mL) at room temperature, was added DBU (17.4 g, 115 mmol). The mixture was stirred at 50° C. for 48 hours before being concentrated in vacuo. Water (200 mL) was then added and the reaction was extracted with EtOAc (×3). The organic layer was washed with brine (500 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 9-33% EtOAc in hexanes to afford the two diastereomers as solids.

Major isomer I-7-1: LRMS (ESI) calc'd for C₂₅H₃₀N₆O₃F [M+H]⁺: 481. found 481. ¹H NMR (600 MHz, DMSO-d6): δ 7.77 (d, J=6.1 Hz, 1H), 7.48 (d, J=6.5 Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 7.29 (t, J=7.2 Hz, 1H), 7.17 (d, J=6.1 Hz, 1H), 5.51 (s, 2H), 5.47 (m, 1H), 5.30 (s, 2H), 4.13 (t, J=13.1 Hz, 1H), 3.91 (d, J=13.1 Hz, 1H), 3.17 (m, 2H), 3.15 (m, 1H), 2.91 (br m, 1H), 2.75 (d, J=15.5 Hz, 1H), 2.05 (t, J=13.0 Hz, 1H), 1.37 (s, 9H). SFC separation was achieved using a ChiralPak OJ-H, with 30% methanol modifier in CO₂: retention times=3.7 (I-7-1A) & 5.7 (I-7-1B) minutes. Minor isomer I-7-2: LRMS (ESI) calc'd for C₂₅H₃₀N₆O₃F [M+H]⁺: 481. found 481. ¹H NMR (600 MHz, DMSO-d6): δ 7.77 (d, J=7.0 Hz, 1H), 7.55 (d, J=7.0 Hz, 2H), 7.43 (t, J=8.2 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 7.25 (d, J=6.7 Hz, 1H), 5.56 (s, 2H), 5.49 (s, 2H), 5.23 (d, J=46.8 Hz, 1H), 4.18 (m, 2H), 3.57 (d, J=17.2 Hz, 1H), 3.46 (d, J=17.3 Hz, 1H), 3.35-3.14 (m, 2H), 2.67 (m, 1H), 2.44 (m, 1H), 1.38 (s, 9H). SFC separation was achieved using a ChiralPak AD-3, with 5-40% ethanol modifier (0.05% DEA in ethanol) in CO₂: retention times=5.4 (I-7-2A) & 6.1 (I-7-2B) minutes.

Following analogous procedure as described above for Intermediate 7-1 and 7-2, the following intermediates shown in Table 3 were prepared. In select cases, the general procedure was modified to alternatively utilize between 1.0-1.5 equivalents DBU, at 25-50° C.

TABLE 3 Intermediate # Structure Compound Name LRMS I-7-3A

2-((3R,4S or 3S, 4R)-3-(3- amino-4-(benzyloxy)-1H- pyrazolo[4,3-c]pyridin-1-yl)- 4-fluorotetrahydro-2H- pyran-3-yl)acetonitrile (Derived from Peak A via SFC: AD-H, 25% MeOH in CO₂, Tr = 4.8 minutes) LRMS (ESI) calc'd for C₂₀H₂₁FN₅O₂ [M + H]⁺: 382, found 382. I-7-3B

2-((3R,4S or 3A,4R)-3-(3- amino-4-(benzyloxy)-1H- pyrazolo[4,3-c]pyridin-1-yl)- 4-fluorotetrahydro-2H- pyran-3-yl)acetonitrile (Derived from Peak B via SFC, AD-H, 25% MeOH in CO₂, Tr = 5.9 minutes) LRMS (ESI) calc'd for C₂₀H₂₁FN₅O₂ [M + H]⁺: 382, found 382.

Intermediate 8 tert-butyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

To a solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (155 g, 645 mmol) in CH₃CN (2.50 L), was added (batchwise) tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (286 g, 1.29 mol) followed by dropwise addition of DBU (99.0 g, 650 mmol) at 20° C. over 20 minutes. The resulting solution was stirred for 3 days at 20° C., concentrated in vacuo at 40-45° C., and then purified by silica chromatography, eluting with 0-50% ethyl acetate/petroleum ether. Concentration of the desired fraction in vacuo afforded compound I-8. LRMS (ESI) calc'd for C₂₅H₃₁N₆O₃ [M+H]⁺: 463. found 463. ¹H NMR (300 MHz, CDCl₃): δ 7.82 (d, 1H), 7.34-7.50 (m, 5H), 6.84 (d, 1H), 5.54 (s, 2H), 4.51 (br s, 2H), 3.94-3.97 (d, 2H), 3.05 (br s, 2H), 2.85-2.90 (m, 2H), 2.79 (s, 2H), 1.92-2.04 (m, 2H), 1.45 (s, 9H).

Intermediate 9 tert-butyl 3-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate

To a solution of 3-amino-1H-pyrazolo[4,3-c]pyridin-4-ol (500 mg, 3.33 mmol) and tert-butyl 3-(cyanomethylidene)azetidine-1-carboxylate (356 mg, 1.83 mmol) in DMF (22.2 mL) was added DBU (0.602 mL, 4.00 mmol). The reaction was heated to 50° C. and allowed to stir for 1 hour, after which a second portion of tert-butyl 3-(cyanomethylidene)azetidine-1-carboxylate (356 mg, 1.83 mmol) was added to the reaction mixture. After an additional 2 hours at 50° C. the reaction was cooled, diluted with water (100 mL) and extracted with 3:1 CHCl₃:IPA (×3). The combined organic layers were washed once with brine (50 mL). The resulting organic layer was dried with Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography, eluting with acetonitrile/water with 0.1% TFA modifier. Fractions containing desired product were diluted with EtOAc, washed with saturated NaHCO₃, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford compound I-9. LRMS (ESI) calc'd for C₁₆H₂₁N₆O₃ [M+H]⁺: 345. found 345. ¹H NMR (600 MHz, DMSO-d6): δ 10.92 (s, 1H), 7.07 (t, J=5.7 Hz, 1H), 6.20 (d, J=7.2 Hz, 1H), 5.46 (s, 2H), 4.35 (m, 2H), 4.15 (m, 2H), 3.28 (s, 2H) 1.34 (s, 9H).

Intermediate 10 tert-butyl 3-[3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate

4-(Benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (8.0 g, 33 mmol) and tert-butyl 3-(cyanomethylidene)azetidine-1-carboxylate (9.7 g, 50 mmol) were dissolved in acetonitrile (200 mL) and DBU (7.6 g, 50 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature, then concentrated in vacuo and purified by silica chromatrography, eluting with 17-67% EtOAc in hexanes. Concentration of the desired fractions afforded compound 1-10, as a solid. LRMS (ESI) calc'd for C₂₃H₂₇N₆O₃ [M+H]⁺: 435. found 435. ¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, J=6.4 Hz, 1H), 7.45 (d, J=7.2 Hz, 2H), 7.30-7.39 (m, 3H), 6.65 (d, J=6.4 Hz, 1H), 5.51 (s, 2H), 4.60 (d, J=9.2 Hz, 2H), 4.52 (s, 2H), 4.22 (d, J=9.6 Hz, 2H), 3.04 (s, 2H), 1.44 (s, 9H).

Intermediate 11 2-(4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)acetonitrile

Step 1: 2-(piperidin-4-ylidene)acetonitrile HCl salt

To tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (2.03 g, 9.15 mmol) was added HCl in dioxane (21 mL, 84 mmol, 4M) and the resulting slurry was stirred at room temperature for 30 minutes, then concentrated in vacuo to afford a crude product that was used as is without further purification. ¹H NMR (600 MHz, DMSO-d6): δ 9.30 (br s, 1H), 5.66 (s, 1H), 3.20-3.10 (m, 4H), 2.67 (t, J=6.1 Hz, 2H), 2.56 (t, J=6.1 Hz, 2H).

Step 2: 2-(1-(2,2-difluoropropanoyl)piperidin-4-ylidene)acetonitrile

To the mixture of 2-(piperidin-4-ylidene)acetonitrile (1.12 g, 9.15 mmol), HATU (5.22 g, 13.7 mmol) in DCM (36.6 mL), was added DIPEA (8.0 mL, 46 mmol) and 2,2-difluoropropanoic acid (2.00 g, 18.3 mmol). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 3% EtOAc in hexanes. Concentration of the desired fraction afforded 2-(1-(2,2-difluoropropanoyl)piperidin-4-ylidene)acetonitrile as a solid. LRMS (ESI) calc'd for C₁₀H₁₃F₂N₂O [M+H]⁺: 215. found 215. ¹H NMR (600 MHz, CDCl₃): δ 5.23 (s, 1H), 3.73-3.75 (m, 4H), 2.62-2.63 (m, 2H), 2.41 (q, J=6.2 Hz, 2H), 1.84 (t, J=19.9 Hz, 3H).

Step 3: 2-(4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)acetonitrile

To a solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (4.76 g, 19.8 mmol) in acetonitrile (45 mL) was added 2-(1-(2,2-difluoropropanoyl)piperidin-4-ylidene)acetonitrile (2.12 g, 9.90 mmol) and DBU (1.49 mL, 9.90 mmol). The reaction mixture was stirred at 40° C. for 72 hours, then concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 43% EtOAc in hexanes. LRMS (ESI) calc'd for C₂₃H₂₅F₂N₆O₂[M+H]⁺: 455. found 455. ¹H NMR (600 MHz, DMSO-d6): δ 7.76 (d, J=6.4 Hz, 1H), 7.52 (d, J=7.5 Hz, 2H), 7.39 (t, J=7.9 Hz, 2H), 7.32 (t, J=7.3 Hz, 1H), 7.20 (d, J=6.3 Hz, 1H), 5.52 (s, 2H), 5.46 (s, 2H), 4.12 (m, 1H), 4.01 (m, 1H), 3.31 (m, 1H), 3.17 (s, 2H), 3.01 (m, 1H), 2.83-2.77 (m, 2H), 2.04-1.94 (m, 2H), 1.79 (t, J=20.1 Hz, 3H).

Intermediate 12 methyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

Step 1: 2-(piperidin-4-ylidene)acetonitrile TFA salt

To a solution of tert-butyl 4-(cyanomethylidene)piperidine-1-carboxylate (3.00 g, 13.5 mmol) in dichloromethane (30 mL) at 20° C., was added trifluoroacetic acid (13.0 g, 115 mmol). The resulting solution was stirred for 1 hour at 20° C. and then concentrated in vacuo to afford an oil that was used as is.

Step 2: methyl 4-(cyanomethylene)piperidine-1-carboxylate

To a solution of crude 2-(piperidin-4-ylidene)acetonitrile TFA salt (3.00 g, 13.7 mmol) in dichloromethane (30 mL), was added triethylamine (7.50 g, 74.1 mmol) and chloro(methoxy)methanone (2.80 g, 29.6 mmol). The resulting solution was stirred for 30 minutes at 20° C. and then concentrated in vacuo. The residue was purified by silica chromatography, eluting with 25% EtOAc in hexanes. Concentration of the desired fractions afforded methyl 4-(cyanomethylidene)piperidine-1-carboxylate as a solid. ¹H NMR (400 MHz, CDCl₃): δ 5.22 (s, 1H), 3.74 (s, 3H), 3.57 (m, 4H), 2.59 (t, J=2.8 Hz, 2H), 2.36 (t, J=2.8 Hz, 2H).

Step 3: methyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (I-12)

To a solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (1.00 g, 4.16 mmol) in ethanol (10 mL), was added methyl 4-(cyanomethylidene)piperidine-1-carboxylate (750 mg, 4.16 mmol) and DBU (630 mg, 4.14 mmol). The resulting solution was stirred for 8 hours at 78° C. The reaction mixture was concentrated in vacuo and purified by silica chromatrography, eluting with 50% EtOAc in hexanes and then the desired fractions were concentrated in vacuo and repurified by preparative TLC using DCM/MeOH=10:1 to afford compound I-12 as a solid. ¹H NMR (400 MHz, CDCl₃): δ 7.86 (d, J=6.4 Hz, 1H), 7.50 (d, J=7.2 Hz, 2H), 7.36-7.44 (m, 3H), 6.86 (d, J=6.4 Hz, 1H), 5.57 (s, 2H), 4.53 (m, 2H), 4.12 (m, 2H), 3.72 (s, 3H), 3.05-3.17 (m, 2H), 2.90-2.98 (m, 2H), 2.82 (s, 2H), 1.96-2.05 (m, 2H).

Intermediate 13 methyl 5-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate

Step 1: methyl 5-oxotetrahydro-2H-pyran-2-carboxylate

To a solution of methyl 5-hydroxy-tetrahydro-2H-pyran-2-carboxylate (487 mg, 3.04 mmol) in CH₂Cl₂ (10 mL), was added Dess-Martin periodinane (1.60 g, 3.80 mmol). The reaction was stirred at room temperature for 2 hours, then diluted with saturated sodium thiosulfate solution and saturated sodium bicarbonate solution and filtered through Celite. The aqueous layer was extracted with CH₂Cl₂ (×2) and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 33% EtOAc in hexanes. Concentration of the desired fractions afforded methyl 5-oxotetrahydro-2H-pyran-2-carboxylate as an oil. ¹H NMR (600 MHz, CDCl₃): δ 4.40 (dd, J=9.2, 4.9 Hz, 1H), 4.32 (d, J=16.9 Hz, 1H), 4.05 (d, J=16.9 Hz, 1H), 3.79 (s, 3H), 2.56 (m, 2H), 2.39 (m, 1H), 2.21 (m, 1H).

Step 2: methyl 5-(cyanomethylene)tetrahydro-2H-pyran-2-carboxylate

A mixture of triethylamine (594 μL, 4.26 mmol), lithium bromide (341 mg, 3.93 mmol) and diethyl (cyanomethyl)phosphonate (379 μL, 2.34 mmol) in THF (5 mL) was stirred for 30 minutes at room temperature. Methyl 5-oxotetrahydro-2H-pyran-2-carboxylate (337 mg, 2.13 mmol) in THF (1 mL) was then added and the reaction mixture was stirred for 12 hours before being quenched with water (5 mL) and extracted with ethyl acetate (×4). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 38% EtOAc in hexanes. Concentration of the desired fractions afforded the title compound (E and Z=5:3) as an oil. LRMS (ESI) calc'd for C₉H₁₂NO₃ [M+H]⁺: 182. found 182. ¹H NMR (600 MHz, DMSO-d6): δ 5.62 (d, J=16.7 Hz, 1H), 4.46 (d, J=13.7 Hz, 0.5H), 4.29 (m, 1.5H), 4.16 (d, J=13.7 Hz, 0.5H), 4.09 (d, J=13.4 Hz, 0.5H), 3.63 (d, J=1.4 Hz, 3H), 2.68 (dt, J=14.7, 4.5 Hz, 0.5H), 2.52 (m, 1.5H), 2.02 (m, 1H), 1.69 (m, 1H).

Step 3: 5-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate

To 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (1.56 g, 6.46 mmol) in acetonitrile (4.3 mL) was added methyl 5-(cyanomethylene)tetrahydro-2H-pyran-2-carboxylate (234 mg, 1.29 mmol) and DBU (195 μL, 1.29 mmol). The reaction mixture was stirred at 40° C. for 72 hours, then concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 33% EtOAc in hexanes. Concentration of the desired fractions afforded compound 1-13 as a solid. LRMS (ESI) calc'd for C₂₂H₂₄N₅O₄ [M+H]⁺: 422. found 422. ¹H NMR (600 MHz, DMSO-d6): δ 7.70 (d, J=6.4 Hz, 1H), 7.46 (d, J=7.6 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.29 (d, J=7.3 Hz, 1H), 7.17 (d, J=6.4 Hz, 1H), 5.48 (s, 2H), 5.40 (s, 2H), 4.29 (dd, J=9.4, 3.9 Hz, 1H), 4.19 (d, J=12.0 Hz, 1H), 4.05 (d, J=11.7 Hz, 1H), 3.66 (s, 3H), 3.32 (m, 1H), 3.28 (d, J=9.1 Hz, 1H), 2.55 (m, 1H), 2.49-2.44 (m, 1H), 1.94-1.78 (m, 2H).

Intermediate 14 tert-butyl 5-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate

Step 1: (2S,5R)-methyl 5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate

To a solution of (2S,5R)-methyl 5-hydroxytetrahydro-2H-pyran-2-carboxylate (3.48 g, 21.7 mmol) in CH₂Cl₂ (90 mL) was added imidazole (2.22 g, 32.6 mmol) and tert-butyldimethylsilyl chloride (3.93 g, 26.1 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with water (50 mL) and extracted with CH₂Cl₂ (×3). The combined organic layers were concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 10% EtOAc in hexanes. Concentration of the desired fractions afforded (2S,5R)-methyl 5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate as an oil. ¹H NMR (600 MHz, CDCl₃): δ 3.97 (ddd, J=11.0, 4.9, 1.9 Hz, 1H), 3.90 (dd, J=11.6, 2.2 Hz, 1H), 3.74 (s, 3H), 3.61 (m, 1H), 3.13 (dd, J=11.0, 9.8 Hz, 1H), 2.06 (m, 2H), 1.68-1.60 (m, 1H), 1.51-1.45 (m, 1H), 0.85 (s, 9H), 0.03 (d, J=6.45 Hz, 6H).

Step 2: (2S,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylic acid

To the solution of (2S,5R)-methyl 5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate (5.40 g, 19.7 mmol) in methanol (55 mL) was added 4N aqueous potassium hydroxide (24.6 mL, 98.4 mmol). The reaction mixture was stirred at room temperature for 2 hours and then the solvent was removed in vacuo. The aqueous residue was acidified to pH-2 using 1N HCl and extracted with chloroform/isopropanol (3:1, ×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford (2S,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylic acid as a solid. LRMS (ESI) calc'd for C₁₂H₂₅O₄Si [M+H]⁺: 261. found 261. ¹H NMR (600 MHz, DMSO-d6): δ 12.56 (s, 1H), 3.78 (dd, J=11.1, 2.9 Hz, 1H), 3.73 (m, 1H), 3.58 (m, 1H), 3.03 (dd, J=10.8, 9.5 Hz, 1H), 1.90 (m, 2H), 1.48-1.40 (m, 2H), 0.81 (s, 9H), 0.05 (d, J=4.1 Hz, 6H).

Step 3: (2S,5R)-tert-butyl 5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate

To a solution of (2S,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylic acid (5.46 g, 19.8 mmol) in toluene (80 mL) at 950 was added 5 mL of a solution of N,N-dimethylformamide di-tert-butyl acetal (19.0 mL, 79 mmol) in toluene (10 mL) under nitrogen. The resulting solution was stirred at 95° C. for 1 hour, at which point the remaining acetal solution was added and the resulting solution was stirred for another 1 hour. The reaction was then concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 10% EtOAc in hexanes. Concentration of the desired fractions afforded (2S,5R)-tert-butyl 5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate as an oil. LRMS (ESI) calc'd for C₁₆H₃₃O₄Si [M+H]⁺: 317. found 317. ¹H NMR (600 MHz, DMSO-d6) δ 3.74 (m, 2H), 3.59 (tt, J=9.7, 4.6 Hz, 1H), 3.02 (dd, J=10.8, 9.5 Hz, 1H), 1.90-1.81 (m, 2H), 1.50-1.41 (m, 2H), 1.38 (s, 9H), 0.81 (s, 9H), 0.02 (d, J=4.7 Hz, 6H).

Step 4: tert-butyl 5-hydroxytetrahydro-2H-pyran-2-carboxylate

To tert-butyl 5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate (4.58 g, 14.5 mmol) was added tetra-n-butylammonium fluoride (72.0 mL, 72.0 mmol, 1M in THF) and the reaction was stirred at room temperature for 2 hours, then concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 44% EtOAc in hexanes. Concentration of the desired fraction afforded tert-butyl 5-hydroxytetrahydro-2H-pyran-2-carboxylate. LRMS (ESI) calc'd for C₁₀H₁₉O₄[M+H]⁺: 203. found 203. ¹H NMR (600 MHz, DMSO-d6): δ 4.79 (d, J=4.8 Hz, 1H), 3.77 (ddd, J=10.7, 4.7, 1.9 Hz, 1H), 3.71 (dd, J=10.9, 2.6 Hz, 1H), 3.40-3.34 (m, 1H), 2.96 (t, J=10.2 Hz, 1H), 1.83 (m, 2H), 1.36 (s, 9H), 1.48-1.13 (m, 2H).

Step 5: tert-butyl 5-oxotetrahydro-2H-pyran-2-carboxylate

To a solution of tert-butyl 5-hydroxytetrahydro-2H-pyran-2-carboxylate (2.85 g, 14.1 mmol) in CH₂Cl₂ (45 mL) was added Dess-Martin periodinane (7.47 g, 17.6 mmol). The reaction was stirred at room temperature for 2 hours, then diluted with saturated sodium thiosulfate and saturated sodium bicarbonate solution. The aqueous layer was extracted with CH₂Cl₂ (×4), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 25% EtOAc in hexanes. Concentration of the desired fractions afforded tert-butyl 5-oxotetrahydro-2H-pyran-2-carboxylate as an oil. ¹H NMR (600 MHz, DMSO-d6): δ 4.31 (dd, J=9.5, 4.6 Hz, 1H), 4.05 (d, J=16.5 Hz, 2H), 2.75 (dt, J=16.8, 5.3 Hz, 1H), 2.37 (dt, J=16.8, 5.3 Hz, 1H), 2.24-2.08 (m, 1H), 1.98 (m, 1H), 1.38 (s, 9H).

Step 6: tert-butyl 5-(cyanomethylene)tetrahydro-2H-pyran-2-carboxylate

A mixture of triethylamine (3.56 mL, 25.6 mmol), lithium bromide (2.05 g, 23.7 mmol) and diethyl (cyanomethyl)phosphonate (2.28 mL, 14.1 mmol) in THF (40 mL) was stirred for 30 minutes at room temperature before tert-butyl 5-oxotetrahydro-2H-pyran-2-carboxylate (2.56 g, 12.8 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature overnight, quenched with water (20 mL), and extracted with ethyl acetate (×4). The combined organic layers was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 25% EtOAc in hexanes. Concentration of the desired fractions afforded tert-butyl 5-(cyanomethylene)tetrahydro-2H-pyran-2-carboxylate as a solid and as a 9:7 mixture of E and Z isomers. LRMS (ESI) calc'd for C₁₂H₁₈NO₃ [M+H]⁺: 224. found 224. ¹H NMR (400 MHz, DMSO-d6): δ 5.61 (d, J=14.9 Hz, 1H), 4.46 (d, J=14.1 Hz, 0.5H), 4.28 (d, J=13.5 Hz, 0.5H), 4.12 (m, 1.5H), 4.06 (d, J=13.4 Hz, 0.5H), 2.70-2.64 (m, 0.5H), 2.66-2.53 (m, 1.5H), 2.05-1.96 (m, 1H), 1.68-1.63 (m, 1H), 1.38 (s, 9H).

Step 7: tert-butyl 5-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate

To a solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (10.8 g, 45.0 mmol) in acetonitrile (35 mL) was added tert-butyl 5-(cyanomethylene)tetrahydro-2H-pyran-2-carboxylate (2.00 g, 8.96 mmol) and DBU (1.35 mL, 8.96 mmol). The vial was sealed and stirred at 40° C. for 72 hours, then concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 43% EtOAc in hexanes. Concentration of the desired fractions afforded tert-butyl 5-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate (Distereomer 1 and 2=3:1), both as solids. Diastereomer I-14-1: LRMS (ESI) calc'd for C₂₅H₃₀N₅O₄ [M+H]⁺: 464. found 464. ¹H NMR (600 MHz, DMSO-d6): δ 7.70 (d, J=6.5 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.17 (d, J=6.5 Hz, 1H), 5.48 (s, 2H), 5.40 (bs, 2H), 4.21 (d, J=11.9 Hz, 1H), 4.11 (dd, J=9.1, 3.7 Hz, 1H), 4.02 (d, J=12.1 Hz, 1H), 3.23 (d, J=4.5 Hz, 2H), 2.45-2.38 (m, 2H), 1.86-1.75 (m, 2H), 1.38 (s, 9H). Diastereomer I-14-2: LRMS (ESI) calc'd for C₂₅H₃₀N₅O₄ [M+H]⁺: 464. found 464. ¹H NMR (600 MHz, DMSO-d6): δ 7.71 (d, J=6.4 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.28 (t, J=7.4 Hz, 1H), 7.13 (d, J=6.4 Hz, 1H), 5.48 (s, 2H), 5.40 (br s, 2H), 4.68 (d, J=14.6 Hz, 1H), 4.15 (dd, J=10.6, 2.9 Hz, 1H), 3.75-3.68 (d, J=12.9 Hz, 1H), 3.00 (d, J=3.9 Hz, 2H), 2.80 (d, J=11.7 Hz, 1H), 2.05-1.95 (m, 1H), 1.85-1.80 (m, 1H), 1.55-1.48 (m, 1H), 1.32 (s, 9H). SFC separation of Diastereomer I-14-1 was performed by Chiralpak IA column 21×250 mm, eluting with 30% methanol in CO₂ to afford Enantiomer 1 (3.06 minutes—I-14-1A) and Enantiomer 2 (4.41 minutes—I-14-1B).

Intermediate 15 2-(8-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,4-dioxaspiro[4.5]decan-8-yl)acetonitrile

To a suspension of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (1.0 g, 4.2 mmol) in MeCN (10 mL) was added 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetonitrile (7.5 g, 42 mmol) and DBU (1.3 g, 8.3 mmol). The resulting reaction mixture was stirred at 55° C. for 41 hours. The reaction mixture volume was reduced by half in vacuo, then purified by silica chromatography, eluting with 0-100 EtOAc in hexanes to give compound 1-15. LRMS (ESI) calc'd for C₂₃H₂₆N₅O₃ [M+H]⁺: 420. found 420. ¹H NMR (600 MHz, DMSO-d6): δ 7.70 (d, J=6.4, 1H), 7.47 (d, J=7.5, 2H), 7.35 (t, J=7.5, 2H), 7.28 (t, J=7.3, 1H), 7.09 (d, J=6.4, 1H), 5.47 (s, 2H), 5.38 (s, 2H), 3.88-3.83 (m, 2H), 3.83-3.78 (m, 2H), 3.03 (s, 2H), 2.71 (d, J=13.9, 2H), 2.03-1.89 (m, 2H), 1.70-1.59 (m, 2H), 1.53-1.41 (m, 2H).

Intermediate 16 2-(1-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile

Step 1: 2-cyclohexylideneacetonitrile

A solution of potassium hydroxide (2.86 g, 51.1 mmol) in acetonitrile (30 mL) was stirred at 80° C. for 5 minutes before a solution of cyclohexanone (5.00 g, 51.0 mmol) in acetonitrile (10 mL) was added dropwise. The resulting solution was stirred for 2 hours at 80° C. and then concentrated in vacuo. The residue was purified by silica chromatography, eluting with 0-1% EtOAc in hexanes to afford 2-cyclohexylideneacetonitrile as an oil. LR GCMS (EI) calc'd for C₈H₁₁N [M]+⁺: 121. found 121.

Step 2: 2-(1-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile

To 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (0.050 g, 0.21 mmol) and 2-cyclohexylideneacetonitrile (0.050 g, 0.42 mmol) in ethanol (0.1 mL) was added DBU (0.031 g, 0.20 mmol). The resulting solution was stirred for 16 hours at 55° C., then concentrated in vacuo to afford crude compound 1-16 as a solid. LRMS (ESI) calc'd for C₂₁H₂₄N₅O [M+H]⁺: 362. found 362.

Intermediate 17 2-(3-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile

To 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (500 mg, 2.08 mmol) in acetonitrile (6.9 mL) was added (E)-2-(dihydro-2H-pyran-3(4H)-ylidene)acetonitrile (436 mg, 3.54 mmol) and DBU (314 μL, 2.08 mmol). The flask was sealed and heated to 40° C. for 24 hours, then concentrated in vacuo and purified by silica chromatography, eluting with 10-100% EtOAc in hexanes. The product was collected and concentrated in vacuo to afford the desired product as a solid. ¹H NMR (600 MHz, CDCl₃): δ 7.81 (d, J=6.4 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.40 (apparent t, J=6.9 Hz, 2H), 7.35 (m, 1H), 7.00 (d, J=6.9 Hz, 1H), 5.53 (s, 2H), 4.49 (s, 2H), 4.21 (d, J=12.1 Hz, 1H), 4.08 (d, J=12.1 Hz, 1H), 3.82 (m, 1H), 3.69 (m, 1H), 3.09 (d, J=18.5 Hz, 1H), 3.01 (d, J=18.5 Hz, 1H), 2.65 (m, 1H), 2.46 (m, 1H), 1.75 (apparent quintet, J=5.8 Hz, 2H). SFC separation was performed by Chiral Technology OJ-H column, eluting with 25% methanol in CO₂ to afford Enantiomer 1 (3.6 minutes—I-17A) and Enantiomer 2 (4.7 minutes—I-17B).

Intermediate 18 2-(1-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile

To a solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (1.7 g, 7.0 mmol) and EtOH (21.5 mL) was added 2-cyclopentylideneacetonitrile I-6-5 (3.8 g, 35 mmol), and DBU (2.1 mL, 14 mmol). The reation mixture was heated to 90° C. for 24 hours, concentrated in vacuo, and the residue was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to afford 1-18. LRMS (ESI) Calc'd for C₂₀H₂₂N₅O [M+H]⁺: 348. found 348. ¹H NMR (CDCl₃, 500 MHz): δ 7.81 (d; J=6.4 Hz, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.41-7.34 (m, 3H), 6.92 (d, J=6.3 Hz, 1H), 5.54 (s, 2H), 4.47 (bs, 2H), 2.88 (s, 2H), 2.67-2.63 (m, 2H), 2.31-2.27 (m, 2H), 1.90-1.82 (m, 4H).

Intermediate 19 2-((1R,2R)-1-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-fluorocyclohexyl)acetonitrile

Step 1: 2-fluorocyclohexanone

To a solution of cyclohexanone (275 g, 2.80 mol) in ACN (2.75 L), under nitrogen, was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.09 kg, 3.08 mol). The resulting solution was stirred for 24 hours at 80° C. The reaction was concentrated in vacuo, and the residue was dissolved in dichloromethane (2.00 L) and the insoluble materials were filtered off. The filtrate was washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, and concentrated in vacuo to afford an oil that was used as is in the next step.

Step 2: 2-(2-fluorocyclohexylidene)acetonitrile

To a solution of diethyl (cyanomethyl)phosphonate (528 g, 2.98 mol) in THF (1.75 L) under nitrogen at 10° C., was added TEA (302 g, 2.98 mol) and LiBr (259 g, 2.98 mol). The resulting solution was stirred for 30 minutes and then a solution of 2-fluorocyclohexan-1-one (350 g, 2.71 mol, 90% pure) in THF (1.75 L) was added dropwise at 10° C. The reaction was stirred at room temperature for 2 hours, diluted with water (300 mL), and the resulting solution was extracted with ethyl acetate (×3). The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 2-5% ethyl acetate/petroleum ether to afford an oil.

Step 3: 2-((1R,2R)-1-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-fluorocyclohexyl)acetonitrile

To a solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (0.22 kg, 0.91 mol) in ACN (635 mL) under nitrogen, was added 2-(2-fluorocyclohexylidene)acetonitrile (0.13 kg, 0.91 mol). DBU (0.139 kg, 0.91 mol) was then added and the solution was stirred for 10 minutes before another batch of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (0.22 kg, 0.91 mmol) was added. The resulting solution was stirred for 48 hours at 50° C. in an oil bath, then diluted with water, and the resulting solution was extracted with ethyl acetate (×3). The combined organic layers were washed with brine (×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with diethyl ether, and the solids were collected by filtration and washed with additional ether. The filtrate was concentrated in vacuo and the residue was purified by silica chromatography, eluting with 20% ethyl acetate/petroleum ether. The desired fractions were combined and reduced in vacuo and the desired product was then recrystallized from disopropyl ether. The racemic cis (fluorine relative to the pyrazolo pyridine) was separated by preparative-SFC using a CHIRALPAK AD-H using 35% ethanol modifier in CO₂. Analytical SFC using a CHIRALPAK AD-H with 15% ethanol modifer in CO₂ gave Tr=3.5 minutes (desired R,R isomer, I-19A) and 4.0 minutes I-19B. LRMS (ESI) calc'd for C₂₁H₂₃FN₅O [M+H]⁺: 380. found: 380. ¹H NMR (300 MHz, CDCl₃): δ 7.72 (d, J=6.3 Hz, 1H), 7.61-7.41 (m, 2H), 7.39-7.21 (m, 3H), 7.17 (d, J=7.5 Hz, 1H), 5.51 (s, 2H), 5.40 (s, 2H), 5.29-4.96 (m, 1H), 3.97-3.23 (m, 2H), 2.73-2.61 (m, 1H), 2.58-2.00 (m, 1H), 1.86 (m, 2H), 1.74-1.66 (m, 2H), 1.59-1.38 (m, 2H).

Intermediate 20 (2S,5S)-5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carb oxylic acid

Step 1: (2S,5S)-tert-butyl 5-(4-(benzyloxy)-3-((4-chlorophenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate

(2S,5S)-tert-butyl 5-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate (500 mg, 1.08 mmol), 4-bromochlorobenzene (248 mg, 1.29 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (92 mg, 0.22 mmol), and potassium acetate (318 mg, 3.24 mmol) were combined in a microwave vial and dissolved in 2-propanol (5 mL). The reaction was degassed by bubbling argon through the solution for 10 minutes, and then Pd₂(dba)₃ (99 mg, 0.11 mmol) was added. The vial was then sealed and stirred at 85° C. overnight. The reaction was then diluted with ethyl acetate and filtered through Celite and concentrated in vacuo. The crude material was purified by silica chromatography, eluting with a 25-75% ethyl acetate in hexanes gradient to afford the title compound. LRMS (ESI) calc'd for C₃₁H₃₃N₅O₄Cl [M+H]⁺: 574. found 574.

Step 2: (2S,5S)-5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylic acid (I-20)

(2S,5S)-tert-butyl 5-(4-(benzyloxy)-3-((4-chlorophenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate (520 mg, 0.906 mmol) was dissolved in hydrochloric acid (5.00 mL, 20.0 mmol, 4M in dioxane) in a 250 mL round bottom flask. The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo to obtain 1-20. LRMS (ESI) calc'd for C₂₀H₁₉ClN₅O₄[M+H]⁺: 428. found: 428. ¹H NMR (500 MHz, DMSO-d6): δ 12.94 (br s, 1H), 11.34 (d, J=5.6 Hz, 1H), 8.35 (s, 1H), 7.74 (d, J=9.2 Hz, 2H), 7.35 (d, J=9.2 Hz, 2H), 7.24 (dd, J=6.2, 7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 4.35 (d, J=11.8 Hz, 1H), 4.28 (dd, J=3.9, 8.6 Hz, 1H), 4.18 (d, J=12.1 Hz, 1H), 3.41 (s, 2H), 2.58 (m, 1H), 2.47 (m, 1H), 1.96 (m, 2H).

Intermediate 21-1 2-(3-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydrofuran-3-yl)acetonitrile

Step 1: 2-(dihydrofuran-3(2H)-ylidene)acetonitrile

To a stirred solution of sodium hydride (1.34 g, 55.8 mmol, 60 wt. % dispersion in mineral oil) in THF (250 mL) was added diethyl (cyanomethyl)phosphonate (9.88 g, 55.8 mmol) by dropwise addition at 0° C. The mixture was stirred at 0° C. for 30 minutes then dihydrofuran-3(2H)-one (4.0 g, 47 mmol) was added by dropwise addition at 0° C. The resulting mixture was stirred for 2 hours at 0° C., then the mixture was diluted with dichloromethane (500 mL) and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 0-5% ethyl acetate in petroleum ether to afford the title compound as a mixture of E and Z isomers. ¹H NMR (400 MHz, CDCl₃): δ 5.39 (s, 1H), 4.60 (s, 2H), 4.07-4.00 (m, 2H), 2.78 (m, 2H). ¹H NMR (400 MHz, CDCl₃): δ 5.36 (s, 1H), 4.46 (s, 2H), 4.03 (m, 2H), 2.92 (m, 2H).

Step 2: 2-(3-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydrofuran-3-yl)acetonitrile

A solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (Intermediate 1, 2.0 g, 8.3 mmol), 2-(dihydrofuran-3(2H)-ylidene)acetonitrile (1.82 g, 16.7 mmol) and DBU (3.80 g, 25.0 mmol) in acetonitrile (20 mL) was refluxed for 16 hours. The mixture was then concentrated in vacuo, and the residue was purified by silica chromatography, eluting with 10% methanol in dichloromethane to afford the title compound. ¹H NMR (400 MHz, CD₃OD): δ 7.81 (d, J=6.4 Hz, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.32-7.42 (m, 3H), 7.06 (d, J=6.4 Hz, 1H), 5.55 (s, 2H), 4.39 (d, J=9.6 Hz, 1H), 4.24 (d, J=9.6 Hz, 1H), 4.04-4.23 (m, 2H), 3.21 (s, 2H), 2.85-2.92 (m, 1H), 2.61-2.68 (m, 1H).

Following the analogous procedure outlined above, the following aryl bromides in Table 4 were prepared.

TABLE 4 Intermediate # Structure Compound Name LRMS 1-21-2

2-(4-(3-amino-4- (benzyloxy)-1H- pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H- pyran-4-yl)acetonitrile LRMS (ESI) calc'd for C₂₀H₂₂N₅O₂ [M + H]⁺: 364, found 364.

Intermediate 22 2-((3R,4R or 3S,4S)-4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile (I-22A) and 2-((3S,4S or 3R,4R)-4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridine-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile (I-22B)

Step 1: 3-fluorodihydro-2H-pyran-4(3H)-one

To a solution of dihydro-2H-pyran-4(3H)-one (20.0 g, 200 mmol) in acetonitrile/water (20/1, 210 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (85.0 g, 240 mmol), and the resulting reaction was stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo and the residue was extracted with EtOAc (×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo, and the residue was purified by silica chromatography, eluting with a 0-100% EtOAc gradient in petroleum ether to afford the title compound as an oil: ¹H NMR (300 MHz, CDCl₃): δ 4.94 (ddd, J=48, 9.6, 6.6 Hz, 1H), 4.42-4.35 (m, 1H), 4.23-4.13 (m, 1H), 3.77-3.61 (m, 2H), 2.76-2.61 (m, 2H).

Step 2: 2-(3-fluorodihydro-2H-pyran-4(3H)-ylidene)acetonitrile

To a solution of diethyl (cyanomethyl)phosphonate (10.8 g, 61.0 mmol) in THF (300 mL) at −20° C., was added dropwise lithium bis(trimethylsilyl)amide (61.0 ml, 61.0 mmol, 1M in THF). The resulting solution was stirred at −20° C. for 30 minutes and 3-fluorodihydro-2H-pyran-4(3H)-one (6.00 g, 40.6 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at −20° C. for 1 hour, then quenched by addition of water (100 mL) and extracted with EtOAc (×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo, and the residue was purified by silica chromatography, eluting with 0-40% EtOAc/petroleum ether to afford the title compound as an oil: ¹H NMR (300 MHz, CDCl₃): δ 5.51 (s, 1H), 5.00 (ddd, J=48.6, 7.9, 5.4 Hz, 1H), 4.15 (m, 1H), 3.99 (m, 1H), 3.59-3.41 (m, 2H), 3.02-2.94 (m, 1H), 2.54 (m, 1H).

Step 3: 2-((3R,4R or 3S,4S)-4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile (I-22A) and 2-((3S,4S or 3R,4R)-4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridine-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile (I-22B)

To a solution of 4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-3-amine (4.00 g, 16.7 mmol) and 2-(3-fluorodihydro-2H-pyran-4(3H)-ylidene)acetonitrile (4.70 g, 33.3 mmol) in acetonitrile (80 mL), was added DBU (5.07 g, 33.3 mmol). The resulting solution was stirred at room temperature for 12 hours, then quenched by addition of water (100 mL), and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 0-40% EtOAc/petroleum ether to afford a racemic mixture of cis and trans product as an oil. The crude product was purified by reversed phase flash chromatography, eluting with 23-41% acetonitrile/water gradient with 0.05% NH₄HCO₃ modifer to afford 2-((3R,4R and 3S,4S)-4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile at 35 minutes and the 2-((3R,4S and 3S,4R)-4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile product at 60 minutes. Resolution of 2-((3R,4R and 3S,4S)-4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile by chiral prep HPLC using a IC column and hexanes:EtOH=80:20 as mobile phase afforded both the enantiomers I-22A at 27 minutes and I-22B at 23 minutes: LRMS (ESI) calc'd for C₂₀H₂₁FN₅O₂[M+H]⁺: 382 found 382; ¹H NMR (300 MHz, CDCl₃): δ 7.84 (d, J=6.6 Hz, 1H), 7.52-7.33 (m, 5H), 6.99 (d, J=6.6 Hz, 1H), 5.56 (s, 2H), 5.09 (d, J=46.2 Hz, 1H), 4.53 (br s, 2H), 4.22-4.15 (m, 1H), 4.07-3.98 (m, 1H), 3.83-3.68 (m, 2H), 3.37 (m, 1H), 3.13 (m, 1H), 3.05 (m, 1H), 2.47 (m, 1H).

Intermediate 23 5-bromo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one

5-Bromo-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0° C. NaH (38 mg, 0.94 mmol, 60 wt. % dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0° C. for 15 minutes before 2,2,2-trifluoroethyl trifluoromethanesulfonate (110 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0° C. for 30 minutes before saturated aqueous NaHCO₃ (10 mL) was carefully added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified silica chromatography, eluting with 0-20% EtOAc in hexanes. Desired fractions were concentrated in vacuo to afford the title compound, 1-23. LRMS (ESI) calc'd for C₁₀H₈BrF₃NO [M+H]⁺: 294. found: 294.

Intermediate 24 N-(4-bromobenzyl)-2,2,2-trifluoroethanamine

To a solution of 4-bromobenzylbromide (0.50 g, 2.0 mmol) in CH₃CN (8.0 mL) was added 2,2,2-trifluoroethanamine (0.60 g, 6.1 mmol) and Cs₂CO₃ (0.97 g, 3.0 mmol). The mixture was stirred at 40° C. for 8 hours, then partitioned between water and EtOAc. The organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 9% EtOAc in hexanes to afford I-24. LRMS (ESI) calc'd for C₉H₁₀NBrF₃ [M+H]⁺: 268. found 268. ¹H NMR (400 MHz, CDCl₃): δ 7.43 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 3.83 (s, 2H), 3.18-3.10 (q, J=9.6 Hz, 2H).

Intermediate 25 (R and S)-1-(4-bromophenyl)-2,2,2-trifluoroethanol

To a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (1.0 g, 3.95 mmol) in THF (10 mL) was added sodium borohydride (164 mg, 4.35 mmol). The mixture was stirred at room temperature for 2 hours, then quenched with water and concentrated in vacuo. The resulting residue was extracted with CH₂Cl₂ (×2), and the combined organic layers were washed with brine (×2), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1-(4-bromophenyl)-2,2,2-trifluoroethanol as a colorless liquid. ¹H NMR (600 MHz, DMSO-d6): δ 7.58 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 6.90 (d, J=5.6 Hz, 1H), 5.16 (m, 1H). Separation of the enantiomers was achieved by SFC using a Chiral Technologies OJ-H, eluting with 5% isopropanol modifier in CO₂. Retention times=4.1 (enantiomer A—Intermediate 25A) & 5.1 (enantiomer B—Intermediate 25B) minutes.

Intermediate 26-1 4-bromo-N-isopropylbenzenesulfonamide

To a solution of propan-2-amine (0.16 g, 2.6 mmol) and DIPEA (0.78 g, 6.0 mmol) in CH₂Cl₂ (7 mL) was added a solution of compound 4-bromophenylsulfonyl chloride (0.51 g, 2.0 mmol) in CH₂Cl₂ (14 mL). The mixture was stirred at room temperature overnight, then poured into water and extracted with CH₂Cl₂ (×3). The organic layer was concentrated in vacuo and the residue was purified by silica chromatography, eluting with 5% EtOAc in hexanes. Concentration of the desired fractions afforded the title compound I-26-1. ¹H NMR (400 MHz, CDCl₃): δ 7.75-7.72 (m, 2H), 7.65-7.62 (m, 2H), 4.43 (d, J=7.5 Hz, 1H), 3.49-3.44 (m, 1H), 1.08 (d, J=6.4 Hz, 6H).

Following the analogous procedure outlined for I-26-1 above, the following aryl bromides in Table 5 were prepared. In certain instances the general procedure was modified by substituting TEA in place of DIPEA, or alternatively conducting the reaction in the absence of base.

TABLE 5 Intermediate # Structure Compound Name LRMS or NMR 1-26-2

N-benzyl-4- bromobenzenesulfon- amide ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J = 5.8 Hz, 2H), 7.70 (d, J = 5.8 Hz, 2H), 7.46-7.44 (m, 3H), 7.27-7.17 (m, 2H), 4.78-4.75 (m, 1H), 4.14 (d, J = 6 Hz, 2H). 1-26-3

4-bromo-N- (cyclopropylmethyl)- benzenesulfonamide ¹HNMR (400 MHz, CDCl₃): δ 7.65 (d, J = 5.6 Hz, 2H), 7.63 (d, J = 5.6 Hz, 2H), 4.48- 4.45 (m, 1H), 2.77-2.73 (m, 2H), 0.81-0.76 (m, 1H) 0.47-0.38 (m, 2H), 0.27-0.25 (m, 2H). 1-26-4

4-bromo-N-(2- methoxyethyl)benzene- sulfonamide ¹H NMR (400 MHz, CDCl₃): δ 7.72 (d, J = 5.8 Hz, 2H), 7.70 (d, J = 5.8 Hz, 2H), 4.48-4.45 (m, 1H), 3.49-3.84 (m, 2H), 3.30 (s, 3H), 3.13- 3.09 (m, 2 H). 1-26-5

4-bromo-N- cyclohexylbenzene- sulfonamide ¹H NMR (400 MHz, CDCl₃): δ 7.75-7.73 (m, 2H), 7.64- 7.6l (m, 2H), 4.70 (d, J = 7.6 Hz, 1H), 3.17-3.09 (m, 1H), 1.75-1.72 (m, 2H), 1.64-1.59 (m, 2H), 1.52-1.48 (m, 1H), 1.24-1.14 (m, 2H). 1-26-6

1-((4- bromophenyl)sulfonyl) piperidine ¹H NMR (400 MHz, CDCl₃): δ 7.66-7.63 (m, 2H), 7.61-7.58 (m, 2H), 2.98-2.95 (m, 4H), 1.66-1.57 (m, 4H), 1.44-1.40 (m, 2H). 1-26-7

4-((4- bromophenyl)sulfonyl) morpholine ¹H NMR (400 MHz, CDCl₃): δ 7.70-7.67 (m, 2H), 7.62-7.59 (m, 2H), 3.74-3.72 (m, 4H), 2.30-2.97 (m, 4H). 1-26-8

4-bromo-N,N,2- trimethylbenzene- sulfonamidc ¹H NMR (600 MHz, CDCl₃): δ 7.75 (d, = 8.1 Hz, 1H), 7.50 (m, 1H), 7.47 (dm, J = 8.3 Hz, 1H), 2.80 (s, 6H), 2.61 (s, 3H). 1-26-9A

(R or S)-1-((4- bromophenyl)sulfonyl)-2- methylpyrrolidine (Separated by SFC, Chiralpak AD-H, 15% MeOH in CO₂, Tr = 3.0 minutes.) LRMS (ESI) calc'd for C₁₁H₁₅BrNO₂S [M + H]⁺: 304, found 304 1-26-9B

(R or S)-1-((4- bromophenyl)sulfonyl)-2- methyl pyrrolidine (Separated by SFC, Chiralpak AD-H, 15% MeOH in CO₂, Tr = 4.4 minutes.) LRMS (ESI) calc'd for C₁₁H₁₅BrNO₂S [M + H]⁺: 304, found 304 1-26-10

1-((4- bromophenyl)sulfonyl)- 2,2-dimethylpyrrolidine LRMS (ESI) calc'd for C₁₂H₁₇BrNO₂S [M + H]⁺: 320, found 320. 1-26-11

1-((4- bromophenyl)sulfonyl) azetidine LRMS (ESI) calc'd for C₉H₁₁BrNO₂S [M + H]⁺: 278, found 278. 1-26-12

1-((4- bromophenyl)sulfonyl)-3- methylazetidine LRMS (ESI) calc'd for C₁₀H₁₃BrNO₂S [M + H]⁺: 292, found 292. 1-26-13

4-bromo-N-isopropyl-N- methylbenzenesulfonamide LRMS (ESI) calc'd for C₁₀H₁₅BrNO₂S [M + H]⁺: 294, found 294. 1-26-14

4-bromo-N-ethyl-N- methylbenzenesulfonamide LRMS (ESI) calc'd for C₉H₁₃BrNO₂S [M + H]⁺: 280, found 280. 1-26-15

ethyl 2-(4-bromo-N- methylphenylsulfonamido)- 2-methylpropanoate ¹H NMR (CDCl₃, 500 MHz): δ 7.86 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 4.25 (q, J = 7.1 Hz, 2H), 2.72 (s, 3H), 1.58 (s, 6H), 1.28 (m, 3H), 1-26-16

4-bromo-N-(tert-butyl)-N- ethylbenzenesulfonamide ¹H NMR (600 MHz, CDCl₃): δ 7.69 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.60 Hz, 2H), 3.48 (q, 2H, J = 7.0 Hz), 1.34 (t, 3H, J = 7.2 Hz), 1.33 (s, 9H). 1-26-17A

(R or S)-1-((4- bromophenyl)sulfonyl)-2- methylazetidine (SFC separation using Chiralpak AD-H, 10% MeOH in CO₂ Tr = 3.9 minutes.) LRMS (ESl) calc'd for C₁₁H₁₃BrNO₂S [M + H]⁺: 292, found 292. 1-26-17B

(R or S)-1-((4- bromophenyl)sulfonyl)-2- methylazetidine (SFC separation using Chiralpak AD-H, 10% MeOH in CO₂ Tr = 4.5 minutes.) LRMS (ESI) calc'd for C₁₁H₁₃BrNO₂S [M + H]⁺: 292, found 292.

Intermediate 27-1 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide

Step 1: 4-bromo-2-methylbenzene-1-sulfonyl chloride

Chlorosulfonic acid (63 g, 0.54 mol) was added slowly to a cold solution (0° C.) of 1-bromo-3-methylbenzene (10.0 g, 58 mmol) in CHCl₃ (100 mL). The reaction was allowed to proceed with stirring for 2 hours at 0° C., then the reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was then washed with brine, dried over NaSO₄, filtered and concentrated in vacuo to afford 4-bromo-2-methylbenzene-1-sulfonyl chloride as a solid. ¹H NMR (400 MHz, CDCl₃): δ 7.90 (d, J=8.4 Hz, 1H), 7.59-7.53 (m, 2H), 2.75 (s, 3H).

Step 2: 4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide

To a solution of 4-bromo-2-methylbenzene-1-sulfonyl chloride (2.0 g, 7.4 mmol) in CH₂Cl₂ (15 mL) was added a solution of 2-methylpropan-2-amine (0.65 g, 8.9 mmol) and triethylamine (0.90 g, 8.9 mmol) in CH₂Cl₂ (30 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 16 hours. The mixture was washed with 0.1 M HCl, saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered and concentrated in vacuo to afford 4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J=8.4 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.59-7.56 (m, 2H), 2.57 (s, 3H), 1.09 (s, 9H).

Step 3: 5-bromo-2-(tert-butyl)benzo [d]isothiazol-3(2H)-one-1,1-dioxide

A mixture of H₅IO₆ (5.9 g, 26 mmol) in acetonitrile (50 mL) was stirred at room temperature for 1 hour, then CrO₃ (33 mg, 0.33 mmol) was added followed by acetic anhydride (2.67 g, 26 mmol). The resulting orange solution was cooled to 0° C., 4-bromo-N-(tert-butyl)-2-methyl benzenesulfonamide (1.0 g, 3.3 mmol) was added. After stirring at 0° C. for 15 minutes, the reaction was allowed to warm to room temperature and was stirred for 16 hours. The solvent was removed in vacuo and the residue was extracted with EtOAc (×3). The combined organic layers were washed with saturated aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 5% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford 5-bromo-2-(tert-butyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 8.82-8.14 (m, 3H), 1.66 (s, 9H).

Step 4: 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole-1,1-dioxide (I-27-1)

To a solution of 5-bromo-2-(tert-butyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide (0.20 g, 0.63 mmol) in THF (4 mL) was added BH₃.Me₂S (240 mg, 3.16 mmol). The reaction mixture was refluxed for 16 hours. After being cooled to room temperature, the reaction was quenched with 2 M HCl, and extracted with EtOAc (×2), the combined extracts were washed with brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC to afford compound I-27-1. ¹H NMR (400 MHz, DMSO-d6) δ 7.83-7.56 (m, 3H), 4.55 (s, 2H), 1.46 (s, 9H).

Following an analogous method to that outlined for I-27-1 above, the following intermediates in Table 6 were prepared:

TABLE 6 Intermediate # Structure Compound Name NMR 1-27-2

5-bromo-2-methyl-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide ¹H NMR (400 MHz, CDCl₃): δ 7.63-7.60 (m, 2H), 7.5 (s, 1H), 4.25 (s, 2H), 2.89 (s, 3H). 1-27-3

5-bromo-2-(2,2,2- trifluoroethyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide ¹H NMR (600 MHz, CDCl₃): δ 7.71 (s, 2H), 7.60 (s, 1H), 4.55 (s, 2H), 3.85 (q, J = 8.4 Hz, 2H). 1-27-4

5-bromo-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide ¹H NMR (600 MHz, DMSO- d6): δ 7.96 (br s, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 4.44 (d, J = 4.8 Hz, 2H).

Intermediate 28 5-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

To a solution of 5-bromo-benzo[b]thiophene 1,1-dioxide (1.0 g, 4.1 mmol) in ethanol (13.6 mL) at 0° C., was added sodium borohydride (193 mg, 5.10 mmol). The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then cooled to 0° C. and quenched with 1N HCl. The mixture was extracted with ethyl acetate (×4) and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The crude oil was purified by silica chromatography, eluting with 20% EtOAc in hexanes to give I-28. ¹H NMR (500 MHz, CDCl₃): δ 7.62-7.53 (m, 2H), 7.51 (s, 1H), 3.55-3.45 (m, 2H), 3.39-3.29 (m, 2H).

Intermediate 29 1-(4-bromophenyl)-2,2,2-trifluoroethanamine

To a solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (1.00 g, 3.95 mmol) in toluene (14 mL) at room temperature, was added (dropwise) a solution of lithium bis(trimethylsilyl)amide (4.35 mL, 4.35 mmol, 1M in THF). The reaction was stirred at room temperature for 15 minutes and then BH₃.THF (7.90 mL, 7.90 mmol, 1M in THF) was added. The reaction was stirred at room temperature for 20 minutes, then quenched at 0° C. by slow addition of 2M aqueous NaOH (5.93 mL, 11.9 mmol). The mixture was stirred at room temperature for 90 minutes, then the organic layer was separated and washed with 1N aqueous NaOH solution, dried over Na₂SO₄, filtered and concentrated in vacuo. SFC separation of the enantiomers on the crude reaction mixture was achieved using a ChiralPak AZ-H, with 7% methanol modifier in CO₂: retention times=2.37 (I-29A) & 2.89 (I-29B) minutes. LRMS (ESI) calc'd for C₈H₈NBrF₃ [M+H]⁺: 254. found 254. ¹H NMR (600 MHz, CDCl₃): δ 7.53 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 4.38 (q, J=7.5 Hz, 1H), 1.78 (br s, 2H).

Intermediate 30-1 1,1′-((5-bromo-1,3-phenylene)bis(methylene))bis(1H-pyrazole)

Step 1: 1-bromo-3,5-bis(bromomethyl)benzene

To 1-bromo-3,5-dimethylbenzene (5.00 g, 27.0 mmol), 1-bromopyrrolidine-2,5-dione (7.20 g, 40.5 mmol), (Z)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.045 g, 0.27 mmol) under nitrogen, was added acetonitrile (80 mL). The resulting solution was stirred for 1 hour at 80° C. and then diluted with saturated aqueous ammonium chloride solution and extracted with dichloromethane (×3). The combined organic layers were concentrated in vacuo and the residue was purified by silica chromatography, eluting with hexanes to afford, after concentration of the desired fractions, 1-bromo-3,5-bis(bromomethyl)benzene as a solid.

Step 2: 1,1′-((5-bromo-1,3-phenylene)bis(methylene))bis(1H-pyrazole)

A solution of 1H-pyrazole (1.80 g, 26.4 mmol) in acetonitrile (120 mL) and potassium carbonate (3.60 g, 26.1 mmol) was stirred under nitrogen at 25° C. for hour, then 1-bromo-3,5-bis(bromomethyl)benzene (3.00 g, 8.75 mmol) was added to the mixture and the solution was stirred for 16 additional hours. The reaction was then quenched by addition of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (×3), and the organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica chromatography, eluting with 50% EtOAc in hexanes. Concentration of the desired fractions affoded compound I-30-1 as a solid. LRMS (ESI) calc'd for C₁₄H₁₄N₄Br [M+H]⁺: 317. found 317.

Following the general procedure outlined above for I-30-1, the intermediates shown in Table 7 were prepared. In certain instances when the benzylic bromide was commercially available, only Step 2 was conducted. In certain instances the displacement reaction step could alternatively be modified by conducting it in the presence of catalytic KI, and/or in acetone at reflux.

TABLE 7 LRMS or Intermediate # Structure Compound Name NMR 1-30-2

2,2′-((5-bromo-1,3- phenylene)bis (methylene))bis(2H-1,2,3- triazole) LRMS (ESI) calc'd for C₁₂H₁₂N₆Br [M + H]⁺: 319, found 319. 1-30-3

1,1′-((5-bromo-1,3- phenylene)bis (methylene))bis(1H-1,2,3- triazole) LRMS (ESI) calc'd for C₁₂H₁₂N₆Br [M + H]⁺ : 319, found 319. 1-30-4

1-(3-((2H-1,2,3-triazol-2-yl) methyl)-5-bromobenzyl)-1H- 1,2,3-triazole LRMS (ESI) calc'd for C₁₂H₁₂N₆Br [M + H]⁺: 319, found 319. 1-30-5

2-(4-bromobenzyl)-2H-1,2,3- triazole ¹H NMR (CDCl₃ 400 MHz): δ 7.62 (s, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8 Hz, 2H), 5.55 (s, 2H). 1-30-6

1-(4-bromobenzyl)-1H-1,2,3- triazole ¹H NMR (CDCl₃ 400 MHz): δ 7.66 (s, 1H), 7.41-7.45 (m, 3H), 7.07 (d. J = 6 Hz, 2H), 5.46 (s, 2H)

Intermediate 31-1 4-bromo-N-(tert-butyl)-N-methylbenzenesulfonamide

To a solution of 4-bromo-N-(tert-butyl)benzenesulfonamide (1.00 g, 3.42 mmol) and potassium carbonate (0.946 g, 6.84 mmol) in DMF (20.0 mL) was added methyl iodide (0.43 mL, 6.8 mmol) at room temperature. The reaction was stirred for 6 hours, then quenched by addition of water and extracted with EtOAc (×3). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo and purified by silica chromatrography, eluting with 0-10% EtOAc in hexanes to give I-31-1 as an oil. LRMS (ESI) calc'd for C₁₁H₁₇NBrO₂SNa [M+Na]⁺: 328. found 328. ¹H NMR (600 MHz, CDCl₃): δ 7.69 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 2.97 (s, 3H), 1.35 (s, 9H).

The following intermediate in Table 8 could made in analogy to I-31-1 above, using Cs₂CO₃ at 50° C. or NaH at 0-25° C.

TABLE 8 Intermediate # Structure Name 1H NMR 1-31-2

tert-butyl 2-(5-bromo-1,1- dioxidobenzo[d]isothiazol- 2(3H)-yl)acetate ¹H NMR (600 MHz, CDCl₃): δ 7.65 (s, 2H), 7.54 (s, 2H), 4.59 (s, 2H), 3.95 (s, 2H), 1.44 (s, 9H).

Intermediates 32 and 33 (R or S) 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (I-32) (R or S) 1-bromo-4-(1,1,1-trifluoro-2-methoxypropan-2-yl)benzene (I-33)

Step 1: (R or S) 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (I-32)

An oven dried round bottom flask with magnetic sir bar under an atmosphere of N₂ was charged with 1-(4-bromophenyl)-2,2,2-trifluoroethanone (2.0 g, 7.9 mmol) and THF (13 mL). The solution was cooled to 0° C., and methyl magnesium bromide (17 mL, 23.7 mmol, 1.4 M in diethyl ether) was added. The reaction mixture was warmed to room temperature over 1-2 hours, and was quenched by the addition of saturated aqueous NH₄Cl (10 mL). The resulting mixture was extracted with Et₂O (×3), and the combined organic layers were concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with hexanes/EtOAc gradient to yield racemic 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol. LRMS (ESI) calc'd for C₉H₉BrF₃O [M+H]⁺: 269. found 269. ¹H NMR (CDCl₃, 500 MHz): δ 7.54 (d, J=8.31 Hz, 2H), 7.47 (d, J=8.26 Hz, 2H), 2.44 (s, 1H), 1.78 (s, 3H). Resolution of enantiomers was achieved by SFC purification using a Chiral Technology AZ-H with 5% MeOH in CO₂. Tr=2.6 minutes (Intermediate I-32A) & 3.2 minutes (Intermediate I-32B).

Step 2: (R or S) 1-bromo-4-(1,1,1-trifluoro-2-methoxypropan-2-yl)benzene (I-33)

An oven dried round bottom flask with magnetic sir bar under an atmosphere of N₂ was charged with 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol I-32A (300 mg, 1.10 mmol) and DMF (3.5 mL). The solution was cooled to 0° C., sodium hydride (67 mg, 1.7 mmol, 60% wt. in mineral oil) was added, and the reaction was stirred for 30 minutes. Iodomethane (0.21 mL, 3.3 mmol) was then added and the reaction mixture was warmed to room temperature over 1-2 hours, quenched by addition of saturated aqueous NH₄Cl (10 mL), and extracted with Et₂O (×3). The combined organic layers were concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with hexanes/EtOAc gradient, to yield I-33A. I-33B was prepared in an analogous manner to I-33A above, using I-32B. ¹H NMR (CDCl₃, 500 MHz): δ 7.54 (d, J=8.19 Hz, 2H), 7.38 (d, J=8.14 Hz, 2H), 3.23 (s, 3H), 1.76 (s, 3H).

Intermediates 34-1 5-bromo-2-cyclopentyl-23-dihydro-1H-isoindol-1-one

Step 1: methyl 4-bromo-2-(bromomethyl)benzoate

To a solution of NBS (38.8 g, 218 mmol) and methyl 4-bromo-2-methylbenzoate (50.0 g, 218 mmol) in CCl₄ (1.00 L) was added AIBN (3.58 g, 21.8 mmol) and the solution was stirred for 16 hours at reflux. The reaction was cooled to ambient temperature, quenched by addition of water (300 mL), and the organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with hexanes:ethyl acetate (100:1) to afford the title compound as a solid. ¹H NMR (300 MHz, CDCl₃) δ 7.81 (d, J=8.4 Hz, 1H), 7.63 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 4.90 (s, 2H), 3.94 (s, 3H).

Step 2: 5-bromo-2-cyclopentyl-2,3-dihydro-1H-isoindol-1-one (I-34-1)

To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (6.00 g, 19.5 mmol), in toluene (100 mL), was added cyclopentylamine (1.83 g, 21.49 mmol) and toluene (100 mL). Triethylamine (3.96 g, 39.1 mmol) was added and the resulting solution was stirred for 16 hours at 110° C. The resulting mixture was cooled to room temperature and concentrated in vacuo and the residue was purified by silica chromatography, eluting with 0.5-1% methanol in dichloromethane to afford I-34-1 as a solid: LCMS (ESI) calc'd for C₁₃H₁₅BrNO [M+H]⁺: 280, 282. found 280, 282; ¹H NMR (400 MHz, CD₃OD) δ 7.81 (s, 1H), 7.70-7.65 (m, 2H), 4.71-4.64 (m, 1H), 4.53 (s, 2H), 2.07-1.91 (m, 2H), 1.89-1.81 (m, 2H), 1.79-1.74 (m, 4H).

The following compounds in Table 9 were prepared in a similar manner as I-34-1 described above.

TABLE 9 Intermediate # Structure Compound Name LCMS or NMR 1-34-2

5-bromo-2-tert- butylisoindolin-1-one LCMS (ESI) calc'd for C₁₂H₁₅BrN [M + H]⁺: 268, 270, found 268, 270; ¹H NMR (300 MHz, CDCl₃): δ 7.65 (s, 1H), 7.57 (m, 2H), 4.43 (s, 2H), 1.59 (s, 9H). 1-34-3

5-bromo-2- cyclohexylisoindolin-1-one LCMS (ESI) calc'd for C₁₄H₁₇BrNO [M + H]⁺: 294, 296, found 294, 296; ¹H NMR (300 MHz, CDCl₃) δ 7.74 (d, J = 7.2 Hz, 1H), 7.60 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 4.33 (s, 2H), 4.23 (m, 1H), 1.87 (m, 4H), 1.73 (m, 1H), 1.50-1.39 (m, 4H). 1-34-4

tert-butyl 2-(5-bromo-1- oxoisoindolin-2-yl)-2- methylpropanoate ¹H NMR (CDCl₃, 500 MHz): δ 7.68 (d, J = 8.0 Hz, 1H), 7.58 (m, 2H), 4.46 (s, 2H), 1.63 (s, 6H), 1.45 (s, 9H).

Intermediate 35-1 ethyl 3-(4-bromophenyl)-4,4,4-trifluoro-3-hydroxy-2,2-dimethylbutanoate

In an oven dried round bottom flask under an atmosphere of nitrogen was charged ethyl isobutyrate (0.69 g, 5.9 mmol) and THF (2.5 mL). The solution was cooled to −78° C., and lithium diisopropylamide (3.0 mL, 5.9 mmol, 2.0 M in THF) was added. The reaction mixture stirred for 30 minutes and then 1-(4-bromophenyl)-2,2,2-trifluoroethanone (0.50 g, 2.0 mmol) was added. The reaction mixture was warmed to room temperature over 1-2 hours, and quenched by the addition of saturated aqueous NH₄Cl. The resulting mixture was extracted with EtOAc (×3), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to yield I-35-1. LRMS (ESI) calc'd for C₁₄H₁₇BrF₃O₃[M+H]⁺: 369. found 369. ¹H NMR (CDCl₃, 500 MHz): δ 7.60 (d, J=8.2 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 4.31-4.27 (m, 2H), 1.38 (d, J=3.5 Hz, 3H), 1.30 (s, 6H).

The following compounds in Table 10 were prepared in a similar manner as I-35-1 described above.

TABLE 10 Intermediate # Structure Compound Name LCMS or NMR 1-35-2

isopropyl 3-(4- bromophenyl)-4,4,4- trifluoro-3-hydroxy-2,2- dimethylbutanoate ¹H NMR (CDCl₃, 500 MHz): δ 7.60 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 4.31 (m, 1H), 1.30 (s, 6H), 1.27 (d, J = 1.2 Hz, 3H), 1.16 (d, J = 1.3 Hz, 3H).

Intermediate 36 5-bromo-2,2-dimethyl-1-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol

Step 1: 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one

To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (0.50 g, 2.4 mmol) in DMF (7.5 mL) at 0° C., was added sodium hydride (237 mg, 5.9 mmol, 60 wt. % dispersion in mineral oil). The reaction mixture stirred for 30 minutes and then iodomethane (0.37 mL, 5.9 mmol) was added. The reaction mixture was warmed to room temperature over 1-2 hours, quenched by addition of saturated aqueous NH₄Cl, and the resulting mixture was extracted with Et₂O (×3). The combined organic layers were concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to afford the title compound. LRMS (ESI) calc'd for C₁₁H₁₂BrO [M+H]⁺: 240. found 240. ¹H NMR (CDCl₃, 500 MHz): δ 7.64-7.61 (m, 2H), 7.53 (d, J=8.2 Hz, 1H), 2.99 (s, 2H), 1.26-1.24 (s, 6H).

Step 2: 5-bromo-2,2-dimethyl-1-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol (I-36)

To a solution of 5-bromo-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (2.2 g, 9.5 mmol) in THF (23 mL) at 0° C., was added (trifluoromethyl) trimethylsilane (7.00 mL, 47.4 mmol) followed by slow (exotherm) addition of tetrabutylammonium fluoride (11.9 mL, 11.9 mmol, 1M in THF). The reaction mixture was warmed to room temperature over 1-2 hours and stirred overnight before being quenched by addition of saturated aqueous NH₄Cl. The resulting mixture was extracted with EtOAc (×3) and the combined organic layers were concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to yield I-36. ¹H NMR (CDCl₃, 500 MHz): δ 7.43-7.41 (m, 2H), 7.33 (d, J=8.1 Hz, 1H), 2.89 (d, J=15.7 Hz, 1H), 2.82 (d, J=15.6 Hz, 1H), 1.27 (s, 3H), 1.16 (s, 3H).

Intermediate 37-1 2-(4-bromophenyl)-1,1,1-trifluoro-3,3-dimethylbutan-2-ol

To a solution of 1-(4-bromophenyl)-2,2-dimethylpropan-1-one (0.20 g, 0.80 mmol) in THF (1 mL) at 0° C., was added (trifluoromethyl) trimethylsilane (0.60 mL, 4.2 mmol) followed by the slow (exotherm) addition of tetrabutylammonium fluoride (0.9 mL, 0.9 mmol, 1M in THF). The reaction mixture was warmed to room temperature over 1-2 hours, and stirred overnight. The reaction was quenched by the addition of saturated aqueous NH₄Cl (10 mL), and the resulting mixture was extracted with EtOAc (×3). The combined organic layers were concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to yield I-37-1. ¹H NMR (CDCl₃, 500 MHz): δ 7.55-7.47 (m, 4H), 1.04 (s, 9H).

The following compounds in Table 11 were prepared in a similar manner as I-37-1 described above.

TABLE 11 Intermediate # Structure Compound Name LRMS or NMR I-37-2A

(S or R) 5-bromo-1- (trifluoromethyl)-2,3- dihydro-1H-inden-1-ol (separated by SFC using a Chiral Technology AZ-H, 5% MeOH in CO2, Peak 1, Tr = 1.7 minutes) ¹H NMR (CDCl₃, 500 MHz): δ 7.43 (m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 3.07 (m, 1H), 3.01-2.95 (m, 1H), 2.67 (m, 1H), 2.24 (m, 1H). LRMS (ESI) calc'd for C₁₀H₉BrF₃O [M + H]⁺: 282, found 282. I-37-2B

(S or R) 5-bromo-1- (trifluoromethyl)-2,3- dihydro-1H-inden-1-ol (separated by SFC using a Chiral Technology AZ-H, 5% MeOH in CO₂, Peak 2, Tr = 2.1 minutes) ¹H NMR (CDCl₃, 500 MHz): δ 7.43 (m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 3.07 (m, 1H), 3.01-2.95 (m, 1H), 2.67 (m, 1H), 2.24 (m, 1H). LRMS (ESI) calc'd for C₁₀H₉BrF₃O [M + H]⁺: 282, found 282.

Intermediate 38 tert-butyl 2-(4-bromo-N-methylphenylsulfonamido)-2-methylpropanoate

Step 1: tert-butyl 2-(4-bromophenylsulfonamido)-2-methylpropanoate

To a solution of 4-bromobenzene-1-sulfonyl chloride (1 g, 4 mmol) in DCM (9 mL) at 0° C., was added triethylamine (1.3 mL, 9.4 mmol) and tert-butyl 2-amino-2-methylpropanoate (0.50 g, 3.1 mmol). The reaction mixture was warmed to room temperature overnight, quenched with saturated aqueous NH₄Cl and diluted with DCM. The organic layer was washed with brine, dried over Na₂SO₄, filtered through Celite, and concentrated in vacuo to afford the title compound that was used as is in the next step. ¹H NMR (CDCl₃, 500 MHz): δ 7.74 (m, 2H), 7.61 (m, 2H), 5.40 (br s, 1H), 1.44 (s, 9H), 1.40 (s, 6H).

Step 2: tert-butyl 2-(4-bromo-N-methylphenylsulfonamido)-2-methylpropanoate (I-38)

To a solution of tert-butyl 2-(4-bromophenylsulfonamido)-2-methylpropanoate (815 mg, 2.2 mmol) in DMF (6.5 mL) at 0° C., was added sodium hydride (129 mg, 3.2 mmol, 60 wt. % dispersion in mineral oil). The reaction mixture was stirred for 30 minutes before methyl iodide (0.40 mL, 6.5 mmol) was added. The reaction was warmed to room temperature over 1-2 hours, then quenched with saturated aqueous NH₄Cl. The reaction was diluted with Et₂O and the organic layer was washed with brine, dried over Na₂SO₄, filtered through Celite, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to afford 1-38. ¹H NMR (CDCl₃, 500 MHz): δ ¹H NMR (500 MHz, CDCl₃): δ 7.86 (m, 2H), 7.63 (m, 2H), 2.72 (s, 3H), 1.48 (s, 15H).

Intermediate 39-1 (4-bromo-2-methylphenyl)(4,4-difluoropiperidin-1-yl)methanone

To a solution of 4-bromo-2-methylbenzoic acid (0.75 g, 3.5 mmol) in DMF (9 mL), was added HATU (2.6 g, 7.0 mmol), Hunig's base (2.4 mL, 14 mmol), and 4,4-difluoropiperidine (0.84 g, 7.0 mmol). The resulting reaction mixture was stirred for 16 hours, concentrated in vacuo, and the crude oil was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to yield I-39-1. ¹H NMR (500 MHz, CDCl₃): δ 7.42-7.37 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 4.02 (m, 1H), 3.82 (m, 1H), 3.36 (m, 2H), 2.30 (s, 3H), 2.11-2.07 (m, 2H), 1.88 (m, 2H).

Table 12 discloses Examples that were prepared in analogy to I-39-1.

TABLE 12 Example Structure Compound Name LRMS I-39-2A

(S or R)-(4-bromo-2- methylphenyl)(3-hydroxy-3- (trifluoromethyl)pyrrolidin- 1-yl)methanone (Derived from Peak 1 via SFC: Chiralpak AS-H, 10% MeOH in CO₂, Tr = 2.57 minutes) LRMS (ESI) Calc'd for C₁₃H₁₄BrF₃NO₂ [M + H]⁺: 354, found 354. I-39-2B

(S or R)-(4-bromo-2- methylphenyl)(3-hydroxy-3- (trifluoromethyl)pyrrolidin- 1-yl)methanone (Derived from Peak 2 via SFC: Chiralpak AS-H, 10% MeOH in CO₂, Tr = 3.10 minutes) LRMS (ESI) Calc'd for C₁₃H₁₄BrF₃NO₂ [M + H]⁺: 354, found 354. I-39-3

(R)-(4-bromo-2-methyl- phenyl)(3-fluoro- pyrrolidin-1-yl) methanone LRMS (ESI) Calc'd for C₁₂H₁₄BrFNO [M + H]⁺: 288, found 288. I-39-4

(S)-(4-bromo-2- methylphenyl)(3- methoxypyrrolidin-1- yl)methanone LRMS (ESI) Calc'd for C₁₃H₁₇BrNO₂ [M + H]⁺: 300, found 300. I-39-5

(R)-(4-bromo-2- methylphenyl)(3- methoxypyrrolidin-1- yl)methanone LRMS (ESI) Calc'd for C₁₃H₁₇BrNO₂ [M + H]⁺: 300, found 300. I-39-6

(4-bromo-2- methylphenyl) (morpholino)methanone LRMS (ESI) Calc'd for C₁₂H₁₅BrNO₂ [M + H]⁺: 286, found 286. I-39-7

(4-bromo-2- methylphenyl) (thiazolidin-3- yl)methanone LRMS (ESI) Calc'd for C₁₁H₁₃BrNOS [M + H]⁺: 288, found 288. I-39-8

(4-bromo-2-methylphenyl) (2-methylthiazolidin-3- yl)methanone LRMS (ESI) Calc'd for C₁₂H₁₅BrNOS [M + H]⁺: 302, found 302. I-39-9

(4-bromo-2-methylphenyl) (2-methylthiomorpholino) methanone LRMS (ESI) Calc'd for C₁₃H₁₇BrNOS [M + H]⁺: 316, found 316. I-39-10

(4-bromo-2-methylphenyl) (thiomorpholino) methanone RH₁₅BrNOS [M + H]⁺: 302, found 302. I-39-11

(4-bromo-2-methylphenyl) (2,2-dimethylmorpholino) methanone LRMS (ESI) Calc'd for C₁₄H₁₉BrNO₂ [M + H]⁺: 312, 314 (1:1), found 312, 314 (1:1).

Intermediate 40-1 8-oxa-3-azabicyclo[3.2.1]octan-3-yl(4-bromo-2-methylphenyl)methanone

Step 1: 4-bromo-2-methylbenzoyl chloride

4-Bromo-2-methylbenzoic acid (1.40 g, 6.50 mmol) was dissolved in thionyl chloride (20 mL). The mixture was stirred at 80° C. for 2 hours and then concentrated in vacuo to afford 1.35 g (crude) of 4-bromo-2-methylbenzoyl chloride as a solid that was used as is in the next step.

Step 2: 8-oxa-3-azabicyclo[3.2.1]octan-3-yl(4-bromo-2-methylphenyl)methanone I-40-1

4-Bromo-2-methylbenzoyl chloride (1.24 g, 5.30 mmol) was added to a suspension of (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane (0.50 g, 4.42 mmol) and triethylamine (2.51 mL, 18.0 mmol) in DCM (10 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with DCM (30 mL) and washed with brine (×2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil that was purified by silica chromatography, eluting with petroleum ether/EtOAc (5/1) to afford the title compound as a solid: LRMS (ESI) calc'd for C₁₄H₁₇BrNO₂ [M+H]⁺: 310 312 (1:1) found 310 312 (1:1); ¹H NMR (300 MHz, CDCl₃): δ 7.41 (s, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 4.76 (m, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.60-3.50 (m, 3H), 2.34 (s, 3H), 2.15-1.86 (m, 4H).

Table 13 discloses Examples that were prepared in analogy to I-40-1.

TABLE 13 Example Structure Compound Name LRMS I-40-2

3-oxa-8 azabicyclo[3.2.1] octan-8-yl (4-bromo-2- methylphenyl) methanone LRMS (ESI) calc'd for C₁₄H₁₇BrNO₂ [M + H]⁺: 310, 312 (1:1) found 310, 312 (1:1).

Intermediate 41 1-bromo-4-(tert-butylsulfonyl)benzene

To a solution of (4-bromophenyl)(tert-butyl)sulfane (1.00 g, 4.08 mmol) in DCM (10.0 mL) was added m-CPBA (2.01 g, 8.97 mmol, 77 wt. %) at room temperature. The resulting solution was stirred at room temperature for one hour and then quenched with saturated aqueous Na₂S₂O₃ and saturated aqueous Na₂CO₃. The reaction was extracted with DCM (×3), dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-41 as a solid. ¹H NMR (600 MHz, DMSO-d6): δ 7.89 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 1.24 (s, 9H).

Intermediate 42-1 N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropan-2-amine

Step 1: 1-(4-bromophenyl)-2,2,2-trifluoroethanol

1-(4-Bromophenyl)-2,2,2-trifluoroethanone (1.73 g, 6.84 mmol) was dissolved in THF (3.4 mL) and treated with sodium borohydride (0.285 g, 7.52 mmol) at 0° C. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with DCM and washed with water and brine. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography, eluting with 5-30% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford the title compound as an oil. ¹H NMR (500 MHz, CDCl₃) δ 7.56 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 5.06-4.96 (m, 1H), 2.63 (d, J=4.5 Hz, 1H).

Step 2: 1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate

A solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanol (1.5 g, 5.9 mmol) and 2,6-lutidine (1.10 mL, 9.41 mmol) in DCE (12 mL) was cooled to −15° C. and triflic anhydride (8.82 mL, 8.82 mmol, 1.0 M in DCM) was added dropwise. The reaction stirred between −15° C. and room temperature for 1 hours, then diluted with DCM and washed with water, 1N aqueous HCl, and brine. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo to give the title compound as a liquid. ¹H NMR (500 MHz, CDCl₃) δ 7.64 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 5.85-5.74 (m, 1H).

Step 3: N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)-2-methylpropan-2-amine (I-42-1)

1-(4-Bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (7.59 g, 19.6 mmol) was dissolved in cyclohexane (70 mL) and 2-methylpropan-2-amine (6.23 mL, 58.8 mmol), DMAP (0.240 g, 1.96 mmol), and ground, dried potassium carbonate (5.42 g, 39.2 mmol) (dried over vacuum at 60° C. for one hour) was added. The reaction mixture was heated to 75° C. and stirred for 48 hours. The reaction mixture was diluted with DCM and washed with water. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography, eluting with 2-20% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford I-42-1 as a liquid. LRMS (ESI) calc'd for Cl₂H₁₆BrF₃N [M+H]⁺: 310. found 310.

Following analogous methodology to that outlined for Intermediate I-42-1 above, the following intermediates in Table 14 were synthesized. In select cases, the general procedure was modified by not using DMAP and/or the crude product was used as is, and/or to alternatively utilize 2.0-3.0 equivalents of amine and/or 1.5-3.0 equivalents of ground, dried potassium carbonate.

TABLE 14 Inter- mediate Structure Name LRMS I-42-2

1-(1-(4- bromophenyl)- 2,2,2-trifluoro- ethyl) pyrrolidine LRMS (ESI) calc'd for C₁₂H₁₄BrF₃N [M + H]⁺: 308, found 308. I-42-3

N-(1-(4- bromophenyl)- 2,2,2-trifluoro- ethyl)propan- 2-amine LRMS (ESI) calc'd for C₁₁H₁₄BrF₃N [M + H]⁺: 296, found 296. I-42-5

1-(4-bromo- phenyl)-N- ethyl-2,2,2- trifluoro- ethanamine LRMS (ESI) calc'd for C₁₀H₁₂BrF₃N [M + H]⁺: 282, found 282. I-42-6

1-(4-bromo- phenyl)-2,2,2- trifluoro-N,N- dimethyl- ethanamine LRMS (ESI) calc'd for C₁₀H₁₂BrF₃N [M + H]⁺: 282, found 282.

Intermediate I-43 2-(4-bromophenyl)-N-isopropylpropan-2-amine

2-(4-Bromophenyl)propan-2-amine (0.5 g, 2.3 mmol) was dissolved in DCM (20 mL) and acetone (2.5 mL). Sodium triacetoxyborohydride (1.5 g, 7.0 mmol) was then added portionwise and the cloudy reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography, eluting with 5-40% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford I-43 as a liquid. LRMS (ESI) calc'd for C₁₂H₁₉BrN [M+H]⁺: 256. found 256.

Intermediate I-44 tert-butyl 3-((4-bromophenyl)sulfonyl)-3-methylbutanoate

1-Bromo-4-(propane-2-sulfonyl)benzene (0.25 g, 0.90 mmol) was dissolved in THF (4.75 mL) and cooled to 0° C. LDA (0.57 mL, 1.1 mmol, 2.0 M in THF) was then added dropwise. The reaction mixture was stirred at 0° C. for 1 hour and then tert-butyl bromoacetate (0.42 mL, 2.85 mmol) was added and the reaction was warmed to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography, eluting with 2-30% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford I-44 as an oil. LRMS (ESI) calc'd for C₁₅H₂₂BrO₄S [M+H]⁺: 377. found 377.

Intermediate I-45 1-(1-(4-bromophenyl)ethyl)pyrrolidine

1-(4-Bromophenyl)ethanone (0.50 g, 2.5 mmol) and pyrroldine (1.04 mL, 12.6 mmol) were dissolved in methanol (8.5 mL) and sodium cyanoborohydride (0.17 g, 2.8 mmol) was added. The reaction was stirred at room temperature over 48 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 5-40% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford I-45. LRMS (ESI) calc'd for C₁₂H₁₇BrN [M+H]⁺: 254. found 254.

Intermediate I-46 1-bromo-4-((2,2-dimethylcyclopentyl)sulfonyl)benzene

Step 1: 2,2-dimethylcyclopentanol

2,2-Dimethylcyclopentanone (0.56 mL, 4.5 mmol) was dissolved in THF (2.0 mL) and methanol (0.5 mL) and cooled to 0° C. Sodium borohydride (0.25 g, 6.7 mmol) was added and the reaction mixture was warmed to room temperature, and stirred for 2 hours. Methanol (1.0 mL) and aqueous NaOH (2.0 mL, 1.0 N) was then added and the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane and washed with water and brine. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 5-40% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford the title compound as a liquid. ¹H NMR (500 MHz, CDCl₃) δ 3.73-3.64 (m, 1H), 2.10-1.98 (m, 1H), 1.80-1.67 (m, 1H), 1.65-1.50 (m, 3H), 1.42-1.35 (m, 1H), 1.32 (d, J=4.2 Hz, 1H), 0.97 (s, 3H), 0.95 (s, 3H).

Step 2: 2,2-dimethylcyclopentyl methanesulfonate

2,2-Dimethylcyclopentanol (257 mg, 2.20 mmol) was dissolved in DCM (4.0 mL) and triethylamine (0.94 mL, 6.8 mmol) was added. The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.26 mL, 3.4 mmol) was added. The reaction was warmed to room temperature and stirred for two hours. Additional triethylamine (0.94 mL, 6.8 mmol) and methanesulfonyl chloride (0.26 mL, 3.4 mmol) were added and the reaction stirred at 40° C. for one hour. Methanesulfonic anhydride (0.59 g, 3.4 mmol) was then added and the reaction was stirred at room temperature for one hour. The reaction mixture was diluted with dichloromethane and washed with aqueous HCl (1.0 N) and brine. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 5-40% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford the title compound as a liquid. ¹H NMR (500 MHz, CDCl₃) δ 4.61-4.55 (m, 1H), 3.00 (s, 3H), 2.22-2.15 (m, 1H), 1.98-1.92 (m, 1H), 1.89-1.79 (m, 1H), 1.74-1.65 (m, 1H), 1.65-1.59 (m, 1H), 1.50-1.43 (m, 1H), 1.06 (s, 3H), 1.02 (s, 3H).

Step 3: (4-bromophenyl)(2,2-dimethylcyclopentyl)sulfane

4-Bromobenzenethiol (170 mg, 0.900 mmol), 2,2-dimethylcyclopentyl methanesulfonate (190 mg, 0.989 mmol), and potassium carbonate (250 mg, 1.80 mmol) were dissolved in DMF (4.5 mL) and the reaction was stirred at 60° C. for 3.5 hours then heated to 100° C. by microwave irradiation for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The combined organic layers were dried over Na₂SO₄, filtered, and the filtrate was concentrated in vacuo to afford the title compound that was sufficiently pure to use in the next step without further purification. ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 3.10 (t, J=8.6 Hz, 1H), 2.26-2.18 (m, 2H), 1.79-1.73 (m, 2H), 1.62 (m, 1H), 1.52-1.46 (m, 1H), 1.08 (s, 3H), 0.99 (s, 3H).

Step 4: 1-bromo-4-((2,2-dimethylcyclopentyl)sulfonyl)benzene (I-46)

(4-Bromophenyl)(2,2-dimethylcyclopentyl)sulfane (0.2 g, 0.7 mmol) was dissolved in DCM (2.0 mL) and mCPBA (0.27 g, 1.5 mmol, 77 wt. % max) was added. The reaction was stirred at room temperature for one hour. The reaction mixture was diluted with dichloromethane and washed with aqueous NaOH (1.0 N) and brine. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 5-30% EtOAc in hexanes and the desired fractions were concentrated in vacuo to afford 1-46 as a solid. LRMS (ESI) calc'd for C₁₃H1₈BrO₂S [M+H]⁺: 317. found 317.

Intermediate 47-1 1-bromo-4-((2,3-dimethylbutan-2-yl)sulfonyl)benzene

To a solution of 1-bromo-4-(isopropylsulfonyl)benzene (100 mg, 0.38 mmol) in dry THF (2 mL) was slowly added LDA (0.19 mL, 0.38 mmol, 2.9 M in THF/heptane/ethylbenzene) at −78° C. After 1.5 hours, iodoethane (91 μL, 1.1 mmol) was added and the mixture was allowed to warm up to room temperature overnight. The mixture was diluted with saturated aqueous ammonium chloride, extracted with ethyl acetate (×3), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 0-40% ethyl acetate/hexanes to afford intermediate I-47-1 as a solid. ¹H NMR (600 MHz, CDCl₃): δ 7.71 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H), 1.71 (q, J=7.6 Hz, 2H), 1.25 (s, 6H), 0.93 (t, J=7.6 Hz, 3H).

The following intermediates in Table 15 were prepared by analogy using the procedure outlined above for I-47-1.

TABLE 15 Inter- mediate Structure Compound Name NMR I-47-2

1-bromo-4-((2,3- dimethylbutan-2- yl)sulfonyl) benzene ¹H NMR (600 MHz, CDCl₃): δ 7.73 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 2.19 (septet, J = 6.4 Hz, 1H), 1.23 (s, 6H), 1.08 (d, J = 6.6 Hz, 6H)

Intermediate 48 1-bromo-4-((S and R)-propan-2-ylsulfonimidoyl)benzene

Step 1: (4-bromophenyl)(isopropyl)sulfane

To 4-bromothiophenol (1.00 g, 5.29 mmol) was added THF (17.6 mL) and then NaH (233 mg, 5.82 mmol, 60 wt %. in mineral oil) and the reaction was stirred at 0° C. for 1 hour before 2-bromopropane (1.24 g, 10.1 mmol) was added. The reaction was stirred overnight, filtered through Celite, and concentrated in vacuo. The residue was then purified on silica, eluting with 2-30% EtOAc/hexanes to afford the desired product as an oil. ¹H NMR (600 MHz, CDCl₃) δ 7.41 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 3.34 (septet, J=6.6 Hz, 1H), 1.29 (d, J=6.6 Hz, 6H).

Step 2: 1-bromo-4-(isopropylsulfinyl)benzene

To (4-bromophenyl)(isopropyl)sulfane (1.25 g, 5.40 mmol) was added CH₂Cl₂ (18.0 mL) and then m-CPBA (1.21 g, 5.40 mmol, 77 wt. % max) at 0° C. The reaction was stirred overnight, then quenched by addition of saturated NaHCO₃ and sodium sulfite solutions. The solution was then stirred for 15 minutes, extracted with DCM (×3), and the organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica, eluting with 2-40% EA/hexanes to afford an oil. ¹H NMR (600 MHz, CDCl₃) δ 7.65 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 2.81 (septet, J=6.6 Hz, 1H), 1.23 (d, J=6.6 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H).

Step 3: 4-methyl-N—[(R and S)-isopropyloxido-(4-bromophenyl)-λ⁴-sulfanylidene]-benzenesulfonamide

Degassed copper(II) trifluoromethanesulfonate (21 mg, 0.057 mmol) and acetonitrile (17.2 mL) along with 1-bromo-4-(isopropylsulfinyl)benzene (175 mg, 0.708 mmol) were stirred under argon for 10 minutes before [N-(p-toluenesulfonyl)imino]phenyliodinane (378 mg, 1.01 mmol) was added and the reaction was stirred at 25° C. overnight, and then at 50° C. for 7 hours. The reaction was concentrated in vacuo, and loaded directly onto silica and eluted with 0-40% EtOAc/hexanes. Concentration of the desired fractions afford the title compound as a foam. LRMS (ESI) calc'd for C₁₆H₁₉NO₃S₂Br [M+H]⁺: 416. found 416. ¹H NMR (600 MHz, CDCl₃) δ 7.80 (m, 4H), 7.73 (d, J=7.5 Hz, 2H), 7.24 (m, 2H), 3.60 (septet, J=6.6 Hz, 1H), 2.37 (s, 3H), 1.35 (d, J=6.6 Hz, 3H), 1.25 (d, J=6.6 Hz, 3H).

Step 4: 1-bromo-4-((S and R)-propan-2-ylsulfonimidoyl)benzene (1-48)

To 4-methyl-N—[(R and S)-isopropyloxido-(4-bromophenyl)-λ⁴-sulfanylidene]-benzenesulfonamide (1.39 g, 3.34 mmol) was added concentrated sulfuric acid (20 mL) at 0° C. and the reaction was stirred at this temperature for 45 minutes, before being allowed to warm to room temperature over 15 minutes. The reaction was then diluted with CH₂Cl₂ and quenched by slow addition of saturated sodium bicarbonate solution. The neutralized solution was then extracted with CH₂Cl₂ (×3), then EtOAc (×2), and the combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. Purification on silica, eluting with 5-80% EtOAc in hexanes afforded an oil. ¹H NMR (600 MHz, CDCl₃): δ 7.80 (m, 4H), 7.81 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 3.27 (septet, J=6.6 Hz, 1H), 1.33 (d, J=7.2 Hz, 3H), 1.28 (d, J=6.6 Hz, 3H).

Intermediate 49 1-(4-bromophenyl)-3,5-dimethyl-1H-pyrazole

Step 1: (4-bromophenyl)hydrazine

A suspension of 4-bromoaniline (100 g, 0.581 mol) in water (500 mL) and concentrated HCl (1.0 L) was charged with a solution of NaNO₂ (40 g, 0.58 mol) in water (250 mL) dropwise at 0° C. over 30 minutes and the resulting reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was then charged to a solution of SnCl₂ (523 g, 2.32 mol) in concentrated HCl (1.0 L) at 0° C. over 30 minutes. The reaction mixture was stirred at room temperature for 3 hours, then cooled to 5° C. and the precipitated solids were filtered and dried at 40° C. to afford the title compound as a solid. ¹H NMR (300 MHz, DMSO-d₆): δ 10.40 (br s, 3H), 7.45 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H).

Step 2: 1-(4-bromophenyl)-3,5-dimethyl-1H-pyrazole (1-49)

A solution of (4-bromophenyl)hydrazine (95 g, 0.42 mol) in EtOH (950 mL) was charged with KOAc (42 g, 0.42 mol) and pentane-2,4-dione (51 g, 0.51 mol) at room temperature and the mixture was heated to reflux for 3 hours. The reaction mixture was then concentrated under reduced pressure and diluted with water (500 mL) and extracted with MTBE (×2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was suspended in hexanes (500 mL) and filtered and the filtrate was concentrated in vacuo to afford I-49 as a liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.58-7.55 (m, 2H), 7.34-7.30 (m, 2H), 6.01 (s, 1H), 2.30 (d, J=5.2 Hz, 6H).

Intermediate 50 1-(4-bromo-2-methylphenyl)-1H-pyrazole

5-Bromo-2-iodotoluene (0.144 mL, 1.01 mmol), pyrazole (68.8 mg, 1.01 mmol), copper(I) oxide (7.2 mg, 0.051 mmol), (1S,2S)-bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine (59.1 mg, 0.202 mmol), and cesium carbonate (658 mg, 2.02 mmol) were combined in a sealed microwave vial, and dissolved in acetonitrile (1.4 mL). The reaction was stirred at 82° C. overnight and then cooled to room temperature and filtered through Celite, rinsing the Celite pad with dichloromethane. The solution was concentrated in vacuo and the crude material was purified by silica chromatrography, eluting with a gradient of 0-25% ethyl acetate in hexanes. LRMS (ESI) calc'd for C₁₀H₁₀N₂Br [M+H]⁺: 237, 239 (1:1). found 237, 239 (1:1). ¹H NMR (500 MHz, CDCl₃): δ 7.72 (s, 1H), 7.57 (s, 1H), 7.47 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.44 (s, 1H), 2.22 (s, 3H).

Intermediate 51-1 6-bromo-N,N-dimethylquinolin-2-amine

6-Bromo-2-chloroquinoline (200 mg, 0.825 mmol) and dimethylamine (2.0 mL, 4.0 mmol, 2M in THF) were combined in a microwave vial and heated at 60° C. overnight. The reaction was diluted with ethyl acetate and washed with water and brine. The organic layer was dried with MgSO₄, filtered, and concentrated in vacuo to the title compound. LRMS (ESI) calc'd for C₁₁H₁₂BrN₂ [M+H]⁺: 251, 253 (1:1). found: 251, 253 (1:1). ¹H NMR (500 MHz, Acetone-d6): δ 7.96 (d, J=9.4 Hz, 1H), 7.84 (s, 1H), 7.61 (dd, J=8.9, 2.2 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.11 (d, J=9.4 Hz, 1H), 3.21 (s, 6H).

The following compounds in Table 16 were prepared using the same procedure as for Intermediate 51-1 above.

TABLE 16 Inter- mediate Structure Compound Name LRMS I-51-2

4-(6-bromoquinolin- 2-yl)morpholine LRMS (ESI) calc'd for C₁₃H₁₄BrN₂O [M + H]⁺: 293, 295 (1:1), found 293, 295 (1:1). I-51-3

(S)-4-(6-bromo- quinolin-2-yl)-2- methylmorpholine LRMS (ESI) calc'd for C₁₄H₁₆BrN₂O [M + H]⁺: 307, 309 (1:1), found 307, 309 (1:1). I-51-4

3-(6-bromoquinolin- 2-yl)-8-oxa-3- azabicyclo[3.2.1] octane LRMS (ESI) calc'd for C₁₅H₁₆BrN₂O [M + H]⁺: 319, 321 (1:1), found 319, 321 (1:1).

Intermediate 52 6-bromo-N,N-dimethylquinoline-2-carboxamide

Step 1: 6-bromoquinoline-2-carboxylic acid

6-Bromo-quinoline-2-carbonitrile (250 mg, 1.07 mmol) was dissolved in MeOH (4.5 mL) in a microwave vial and 5N aqueous sodium hydroxide (1.5 mL, 2.25 mmol) was added. The reaction was heated at 100° C. for 20 minutes, then cooled to room temperature and concentrated in vacuo. The residue was acidified to pH 5 using 1M aqueous HCl and the reaction was extracted using ethyl acetate (×1). The organic layer was then dried using MgSO₄, filtered, and concentrated in vacuo to giv the title compound. ¹H NMR (500 MHz, DMSO-d6): δ 13.58 (br s, 1H), 8.57 (d, J=8.5 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.13 (d, J=9.3 Hz, 1H), 8.02 (dd, J=9.3, 2.2 Hz, 1H).

Step 2: 6-bromo-N,N-dimethylquinoline-2-carboxamide

6-Bromoquinoline-2-carboxylic acid (40 mg, 0.16 mmol) and HATU (121 mg, 0.317 mmol) were dissolved in DMF (0.50 mL) and stirred at room temperature for 5 minutes. A separate solution of DMF (0.50 mL), dimethylamine (0.159 mL, 0.317 mmol, 2M in THF)) and DIPEA (0.083 mL, 0.48 mmol) was then added and the reaction was stirred at room temperature for 1 hour before being diluted with EtOAc, and washed with water. The organic layer was then dried using MgSO₄, filtered, and concentrated in vacuo to give the title compound. ¹H NMR (500 MHz, CDCl₃): δ 8.17 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 3.20 (s, 3H), 3.16 (s, 3H).

Intermediate 53 6-bromoquinoline-2-carboxamide

Potassium carbonate (59.3 mg, 0.429 mmol) and hydrogen peroxide (0.31 mL, 3.0 mmol) were dissolved in acetonitrile (2.0 mL). 6-Bromo-quinoline-2-carbonitrile (100 mg, 0.429 mmol) was then added. The reaction was stirred at room temperature overnight and then additional hydrogen peroxide (0.22 mL, 2.2 mmol) was added to the reaction mixture which was then heated at 50° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over MgSO₄, filtered, and concentrated in vacuo to give the title compound. ¹H NMR (500 MHz, CDCl₃): δ 8.33 (d, J=8.5 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.03 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.85 (dd, J=8.8, 2.5 Hz, 1H), 5.74 (br s, 1H).

Intermediates I-54A and I-54B (R or S)-2-(4-bromophenyl)-2-(trifluoromethyl)piperidine

Step 1: 4-bromobenzoyl chloride

A solution of 4-bromobenzoic acid (10.0 g, 49.7 mmol) in sulfurous dichloride (59.2 g, 0.50 mol) was heated at 80° C. for 16 hours. The mixture was then concentrated in vacuo to afford the title compound which was carried onto the next step without further purification.

Step 2: tert-butyl 3-(4-bromobenzoyl)-2-oxopiperidine-1-carboxylate

Lithium bis(trimethylsilyl)amide (2.11 mL, 2.11 mmol, 1.0 M in THF) was added to a solution of tert-butyl 2-oxopiperidine-1-carboxylate (0.20 g, 1.0 mmol) in THF (2 mL) at −78° C. The resulting mixture was stirred for 10 minutes, then 4-bromobenzoyl chloride (0.22 g, 1.0 mmol) was added. The reaction was warmed to ambient temperature and stirred for 1 hour, then saturated aqueous ammonium chloride (20 mL) was added. The quenched reaction was extracted with EtOAc (×3) and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified on silica, eluting with 0-1% EtOAc in hexanes to afford the title compound. LRMS (ESI) calc'd for: C₁₇H₂₁BrNO₄ [M+H]⁺: 382, 384 (1:1). found 382, 384 (1:1).

Step 3: 6-(4-bromophenyl)-2,3,4,5-tetrahydropyridine

tert-Butyl 3-(4-bromobenzoyl)-2-oxopiperidine-1-carboxylate (2.00 g, 5.23 mmol) was combined with HCl (8.0 M, 43.6 mL, 0.52 mol) at ambient temperature. The resulting solution was heated at 80° C. for 16 hours. The reaction was then poured into saturated aqueous Na₂CO₃ (50 mL) and extracted with EtOAc (×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified on silica, eluting with 0-1% EtOAc in hexanes to afford the title compound. LRMS (ESI) calc'd for: C₁₁H₁₃BrN [M+H]⁺: 238, 240 (1:1). found 238, 240 (1:1); ¹H NMR (300 MHz, CDCl₃) δ 7.66-7.63 (m, 2H), 7.52-7.47 (m, 2H), 3.90 (m, 2H), 2.59 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.66 (m, 2H).

Step 4: (R or S)-2-(4-bromophenyl)-2-(trifluoromethyl)piperidine and (R or S)-2-(4-bromophenyl)-2-(trifluoromethyl)piperidine (I-54A and I-54B)

To a solution of 6-(4-bromophenyl)-2,3,4,5-tetrahydropyridine (1.0 g, 4.2 mmol) in acetonitrile (10 mL), was successively added trifluoromethanesulfonic acid (3.30 g, 22.0 mmol), potassium hydrogen fluoride (3.94 g, 50.4 mmol) and trimethyl(trifluoromethyl)silane (5.97 g, 42.0 mmol) at 0-4° C. The resulted mixture was stirred at ambient temperature for 48 hours. The reaction was then quenched with saturated aqueous NaHCO₃ (50 mL) followed by extraction with EtOAc (×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified on silica, eluting with 0-1% DCM in petroleum ether to afford the racemic title compound. The title compounds were then separated by SFC using a Chiralpak IA column, eluting with 15% i-PrOH in CO₂ to afford Peak A (I-54A) (Tr=4.7 minutes) and Peak B (I-54B) (Tr=5.5 minutes). LRMS (ESI) calc'd for C₁₂H₁₄BrF₃N [M+H]⁺: 308, 310 (1:1). found 308, 310 (1:1); ¹H NMR (300 MHz, CDCl₃): δ 7.66 (m, 2H), 7.59 (m, 2H), 3.16-3.03 (m, 1H), 2.73-2.63 (m, 1H), 2.50-2.42 (m, 1H), 2.25-1.93 (m, 1H), 1.75 (m, 1H), 1.67-1.53 (m, 3H), 1.33 (m, 1H).

Intermediates I-55A and I-55B (R) and (S)-2-(4-bromophenyl)-2-(trifluoromethyl)pyrrolidine

Step 1: 3-(4-bromobenzoyl)-1-vinylpyrrolidin-2-one

Potassium tert-butoxide (6.26 g, 55.80 mmol) was added to a solution of 1-vinylpyrrolidin-2-one (6.20 g, 55.8 mmol) and methyl 4-bromobenzoate (10.00 g, 46.50 mmol) in THF (150 mL). The mixture was stirred at ambient temperature for an hour at which time water (200 mL) was added and the pH was adjusted to 7 with aqueous hydrochloric acid (1 M). The resulting mixture was extracted with EtOAc (×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica chromatography, eluting with 0-20% EtOAc in petroleum ether to afford the title compound as a solid. LRMS (ESI) calc'd for C₁₃H₁₃BrNO₂ [M+H]⁺: 294, 296 (1:1). found 294, 296 (1:1); ¹H NMR (300 MHz, CDCl₃): δ 7.90 (d, J=6.6 Hz, 2H), 7.65 (d, J=6.6 Hz, 2H), 7.06-6.97 (m, 1H), 4.53 (m, 3H), 3.77-3.68 (m, 1H), 3.59 (m, 1H), 2.80-2.71 (m, 1H), 2.37-2.28 (m, 1H).

Step 2: 5-(4-bromophenyl)-3,4-dihydro-2H-pyrrole

A suspension of 3-(4-bromobenzoyl)-1-vinylpyrrolidin-2-one (5.00 g, 17.0 mmol) in aqueous HCl (20 mL, 8 M) was heated at reflux for 16 hours. The mixture was cooled to ambient temperature and extracted with EtOAc (×3). The aqueous layer was basified to pH=13 with NaOH (15% aqueous solution) and then extracted with DCM (×5). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica chromatography, eluting with 0-20% EtOAc in petroleum ether the title compound as a solid. LRMS (ESI) calc'd for C₁₀H₁₁BrN [M+H]⁺: 224, 226 (1:1). found 224, 226 (1:1); ¹H NMR (300 MHz, CDCl₃): δ 7.74-7.69 (m, 2H), 7.54 (m, 2H), 4.06 (m, 2H), 2.96-2.88 (m, 2H), 2.10-2.00 (m, 2H).

Step 3: (S) and (R)-2-(4-bromophenyl)-2-(trifluoromethyl)pyrrolidine

To an ice-cooled solution of 5-(4-bromophenyl)-3,4-dihydro-2H-pyrrole (0.80 g, 3.6 mmol) in dry acetonitrile (3 mL) was successively added trifluoromethanesulfonic acid (0.67 g, 4.5 mmol), potassium hydrogen fluoride (0.840 g, 10.7 mmol) and trimethyl(trifluoromethyl) silane (5.08 g, 35.7 mmol). The reaction solution was warmed to ambient temperature and stirred for 48 hours before being quenched with saturated aqueous NaHCO₃ until pH>7. The solution was extracted with EtOAc (×3) and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 0-20% DCM in petroleum ether to afford the title compound as an oil. LRMS (ESI) calc'd for C₁₁H₁₂BrF₃N [M+H]⁺: 294, 296 (1:1). found 294, 296 (1:1); ¹H NMR (300 MHz, CDCl₃): δ 7.49 (d, J=5.4 Hz, 2H), 7.42 (d, J=5.4 Hz, 2H), 3.29-3.21 (m, 1H), 3.16-3.08 (m, 1H), 2.60-2.51 (m, 1H), 2.25-2.16 (m, 1H), 2.08-1.94 (m, 1H), 1.89-1.75 (m, 1H). This racemic mixture was resolved by chiral HPLC using a Chiralpak AD-H column and methanol (with 0.2% DEA modifier) to Peak 1 (I-55A, retention time=4.4 minutes) and Peak 2 (I-55B, retention time=5.2 minues).

Intermediate 56 tert-butyl 4-(5-bromo-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)piperidine-1-carboxylate

Step 1: 4-bromo-2-(bromomethyl)benzene-1-sulfonyl chloride

To a solution of N-bromosuccinimide (26.4 g, 148 mmol) and 4-bromo-2-methylbenzene-1-sulfonyl chloride (20.0 g, 74.2 mmol) in carbon tetrachloride (1.00 L) was added 2,2′-azobis(2-methylpropionitrile) (2.43 g, 14.8 mmol) at ambient temperature. The reaction mixture was stirred at 80° C. for 16 hours under argon, then cooled and the solids filtered. To the filtrate was then charged another portion of N-bromosuccinimide (26.4 g, 148 mmol) and 2,2′-azobis(2-methylpropionitrile) (2.43 g, 14.8 mmol) and the reaction was stirred at 80° C. for an additional 16 hours under argon. The solids were again filtered, and the filtrate was concentrated in vacuo. The residue was used next step without further purification.

Step 2: tert-butyl 4-(4-bromo-2-(bromomethyl)phenylsulfonamido)piperidine-1-carboxylate

To a solution of 4-bromo-2-(bromomethyl)benzene-1-sulfonyl chloride (60.0 g, 172 mmol) in DCM (1.00 L) was added a solution of tert-butyl 4-aminopiperidine-1-carboxylate (20.7 g, 103 mmol) and triethylamine (34.8 g, 344 mmol) in DCM (100 mL) at ambient temperature. The mixture was stirred at ambient temperature for 3 hours, then quenched with water (500 mL), extracted with DCM (×3), and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica chromatography, eluting with 25% EtOAc in petroleum ether to afford the title compound as a solid. LRMS (ESI) calc'd for C₁₃H₁₇Br₂N₂O₄S [M−t-Bu+H]⁺: 455, 457, 459 (1:2:1) found 455, 457, 459 (1:2:1).

Step 3: tert-butyl 4-(5-bromo-1,1-dioxidobenzo[d]isothiazol-2(3)-yl)piperidine-1-carboxylate (I-56)

To a room temperature solution of tert-butyl 4-(4-bromo-2-(bromomethyl)phenylsulfonamido)piperidine-1-carboxylate (50.0 g, 98.0 mmol) in acetonitrile/water (3/1, 400 mL), was added sodium bicarbonate (24.6 g, 293 mmol). The mixture was stirred at 80° C. for 16 hours and then concentrated in vacuo. The residue was diluted with water (200 mL), extracted with EtOAc (×3), and the combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica chromatography, eluting with 20% ethyl acetate in petroleum ether to afford the title compound as a solid. LRMS (ESI) calc'd for C₁₃H₁₆BrN₂O₄S [M−t-Bu+H]⁺: 375, 377 (1:1) found 375, 377 (1:1); 1H NMR (400 MHz, CD₃OD): δ 7.76 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 4.44 (s, 2H), 4.08 (d, J=13.5 Hz, 2H), 3.78-3.71 (m, 1H), 2.98-2.83 (m, 2H), 2.00-1.94 (m, 2H), 1.85-1.73 (m, 2H), 1.43 (s, 9H).

Intermediate 57 5-bromo-2-(N-trifluoroethylpiperidine-4-yl)cyclohexyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

Step 1: 5-bromo-2-(piperidine-4-yl)cyclohexyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

To 5-bromo-2-(N-tert-butyl carbomatepiperidine-4-yl)cyclohexyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate 56) (0.10 g, 0.23 mmol), was added a solution of hydrogen chloride gas in EtOAc (5 mL) at ambient temperature. The reaction was maintained at the same temperature for an additional hour at which time the precipitate was collected by filtration and washed with EtOAc to give the title compound as an HCl salt as solid. It was then used in the next step without further purification. LRMS (ESI) calc'd for C₁₂H₁₆BrN₂O₂S [M+H]⁺: 331, 333 (1:1). found 331, 333 (1:1).

Step 2: 5-bromo-2-(N-trifluoroethylpiperidine-4-yl)cyclohexyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (I-57)

5-Bromo-2-(piperidine-4-yl)cyclohexyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (50 mg, 0.15 mmol), diisopropylethylamine (60 mg, 0.47 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.10 g, 0.43 mmol) were combined with acetonitrile (15 mL) at ambient temperature. The resulting solution was maintained at the same temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in water (30 mL) and extracted with EtOAc (×3). The organic layers were combined, dried over Na₂SO₄, filtered, concentrated in vacuo and the residue purified by silica chromatography, eluting with EtOAc/petroleum ether (2/5) to give the title compound as a solid. LRMS (ESI) calc'd for C₁₄H₁₇BrF₃N₂O₂S [M+H]⁺: 413, 415 (1:1). found 413, 415 (1:1); ¹H NMR (400 MHz, CDCl₃): δ 7.67 (m, 2H), 7.58 (s, 1H), 4.38 (s, 2H), 3.76-3.68 (m, 1H), 3.13-3.02 (m, 4H), 2.68-2.56 (m, 2H), 2.05 (m, 4H).

Intermediate 58 (R and S)-1-benzyl-3-(4-bromophenyl)-3-(trifluoromethyl)pyrrolidine

Step 1: 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene

To a solution of methyltripenylposphonium bromide (6.35 g, 17.8 mmol) in THF (13.2 mL) under nitrogen at 0° C., was added lithium bis(trimethylsilyamide (17.8 mL, 17.8 mmol, 1M in THF). The reaction mixture was stirred for 30 minutes, then cooled to −78° C. 1-(4-bromophenyl)-2,2,2-trifluoroethanone (3 g, 11.86 mmol) was then added and the reaction mixture was allowed to warm to room temperature over 1 hour. Then reaction was poured into 1:1 ice water/NH₄Cl, and the aqeuous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the title compound. ¹H NMR (600 MHz, CDCl₃): δ 7.50 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 5.96 (s, 1H), 5.75 (s, 1H).

Step 2: (R and S) 1-benzyl-3-(4-bromophenyl)-3-(trifluoromethyl)pyrrolidine (I-58)

To a solution of 1-bromo-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.25 g, 1.0 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (0.51 mL, 2.0 mmol) in DCM (5 mL) at 0° C., was added trifluoroacetic acid (7.7 μL, 0.1 mmol). The reaction mixture was stirred and warmed to room temperature over 3 hours. Then reaction was quenched with saturated aqueous NaHCO₃ (20 mL), and the aqeuous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the title compound. ¹H NMR (600 MHz, CDCl₃): δ 7.45 (d, J=8.2 Hz, 2H), 7.29-7.35, (m, 4H), 7.19-7.23 (m, 3H), 3.65-3.67 (m, 2H), 3.18 (m, 1H), 2.77 (m, 1H), 2.58 (m, 1H), 2.37 (m, 1H), 1.25 (m, 1H), 0.85 (m, 1H).

Example 1-1 tert-butyl 3-(cyanomethyl)-3-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate

3-(Phenylamino)-1H-pyrazolo[4,3-c]pyridin-4(5H)-one (11.3 mg, 0.0499 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (17.0 mg, 0.088 mmol) were dissolved in DMF (1.0 mL). DBU (14 μL, 0.093 mmol) was added and the reaction mixture was stirred overnight at room temperature. After 18 hours the reaction mixture was diluted in EtOAc and washed with saturated aqueous sodium hydrogen carbonate and brine. The combined aqueous layers were back extracted with 3:1 chloroform/isopropanol (×1) and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with a 10-100% EtOAc/isohexane, followed by a 0-5% MeOH/EtOAc gradient to afford compound 1-1. LRMS (ESI) calc'd for C₂₂H₂₅N₆O₃ [M+H]⁺: 421. found 421. ¹H NMR (600 MHz, DMSO-d6): δ 11.28 (s, 1H), 8.06 (s, 1H), 7.62-7.56 (m, 2H), 7.28-7.19 (m, 3H), 6.86 (dd, J=7.2, 6.6 Hz, 1H), 6.36 (dd, J=7.2, 1.8 Hz, 1H), 4.46 (d, J=8.4 Hz, 2H), 4.25 (d, J=6.6 Hz, 2H), 3.41 (s, 2H), 1.36 (s, 9H).

The following examples outlined in Table 17 were prepared by analogy using the general procedure outlined above for Example 1-1, using 1.2 equivalents DBU, 1.5 equivalents Michael acceptor in DMF (0.15 M) at 50° C.

TABLE 17 Example Structure Compound Name LRMS 1-2

tert-butyl 4- (cyanomethyl)-4-(4- oxo-3-(phenylamino)- 4,5-dihydro-1H- pyrazolo[4,3-c] pyridin-1-yl) piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₄H₂₉N₆O₃ [M + H]⁺: 449, found 449.

tert-butyl 4-(cyanomethyl)-4-[3-(ethylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate

Step 1: tert-butyl 4-(4-(benzyloxy)-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-[3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate (20 mg, 0.043 mmol) in dichloroethane (0.30 mL) was added a solution of acetaldehyde (3.0 μL, 0.054 mmol) and acetic acid (2.5 μL, 0.043 mmol) in dichloroethane (0.24 mL). This mixture was stirred at room temperature for 10 minutes before sodium triacetoxyborohydride (16 mg, 0.076 mmol) was added. The reaction was stirred at room temperature for 5.5 hours, then diluted with EtOAc and washed with 1N NaOH and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo.

The residue was purified by silica chromatography, eluting with 0-100% EtOAc/hexanes to afford Example 2-la. LRMS (ESI) calc'd for C₂₇H₃₅N₆O₃ [M+H]⁺: 491. found 491.

Step 2: tert-butyl 4-(cyanomethyl)-4-[3-(ethylamino)-4-oxo-4,5-dihydro-1H-pyrazolo-[4,3-c]pyridin-1-yl]piperidine-1-carboxylate

tert-Butyl 4-(4-(benzyloxy)-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (2-la) (9.0 mg, 0.018 mmol) was dissolved in EtOAc (2.0 mL) and EtOH (0.20 mL). Pd/C (10 mg, 0.094 mmol) was added and the reaction was stirred under 1 atmosphere of hydrogen for 2 hours. The reaction was then filtered through Celite and washed with DCM and the filtrate was concentrated in vacuo. The crude reaction mixture was purified by silica chromatrography, eluting with 100% EtOAc. Concentration of the desired fractions afforded compound 2-1. LRMS (ESI) calc'd for C₂₀H₂₉N₆O₃ [M+H]⁺: 401. found 401. ¹H NMR (600 MHz, DMSO-d6): δ 10.93 (d, J=5.0 Hz, 1H), 7.01 (t, J=6.6 Hz, 1H), 6.49 (d, J=7.5 Hz, 1H), 5.42 (t, J=5.8 Hz, 1H), 3.68 (d, J=13.8 Hz, 2H), 3.18 (dt, J=13.4 Hz, 6.8, 2H), 3.10 (s, 2H), 2.98 (br s, 2H), 2.57 (d, J=13.9 Hz, 2H), 1.85 (t, J=10.2 Hz, 2H), 1.35 (s, 9H), 1.12 (t, J=7.1 Hz, 3H).

The following Examples shown in Table 18 were prepared in analogy to Example 2-1 above:

TABLE 18 Example Structure Compound Name LRMS 2-2

tert-butyl 4-(cyanomethyl)- 4-{3-[(cyclopropylmethyl) amino]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₂H₃₁N₆O₃ [M + H]⁺: 427, found 427 2-3

tert-butyl 4-(cyanomethyl)- 4-[3-(cyclobutylamino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₂H₃₁N₆O₃ [M + H]⁺: 427, found 427 2-4

tert-butyl 3-(cyanomethyl)- 3-[3-(ethylamino)-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl] azetidine-1-carboxylate LRMS (ESI) calc'd for C₁₈H₂₅N₆O₃ [M + H]⁺: 373, found 373 2-5

tert-butyl 4-(cyanomethyl)- 4-[3-(methylamino)-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl] piperidine-1-carboxylate LRMS (ESI) calc'd for C₁₉H₂₇N₆O₃ [M + H]⁺: 387, found 387

Example 3 tert-butyl 3-(cyanomethyl)-3-[3-(cyclopropylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]azetidine-1-carboxylate

Step 1: tert-butyl 3-[4-(benzyloxy)-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate

To a solution of tert-butyl 3-[3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate (250 mg, 0.575 mmol) in dichloroethane (10 mL) was added I₂ (365 mg, 1.44 mmol). The mixture was stirred for 10 minutes under nitrogen and was then cooled to 0° C. and tert-butyl nitrite (0.137 mL, 1.15 mmol) was added dropwise. The reaction was stirred at 0° C. for 10 minutes, then warmed to room temperature and stirred for 2 additional hours. The reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO₃, brine, saturated aqueous NaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 0-75% EtOAc in hexanes to afford compound 3a. LRMS (ESI) calc'd for C₂₃H₂₅IN₅O₃ [M+H]⁺: 546. found 546. ¹H NMR (600 MHz, CDCl₃): δ 7.96 (d, J=6.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.38 (t, J=7.8 Hz, 2H), 7.31 (t, J=7.2 Hz, 1H), 6.87 (d, J=6.6 Hz, 1H), 5.59 (s, 2H), 4.66 (d, J=9.6 Hz, 2H), 4.33 (d, J=9.0 Hz, 2H), 3.16 (s, 2H), 1.44 (s, 9H).

Step 2: tert-butyl 3-[4-(benzyloxy)-3-(cyclopropylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate

A vial equipped with a stir bar was charged with CuI (4.4 mg, 0.023 mmol), potassium phosphate tribasic (24.3 mg, 0.115 mmol), L-proline (5.3 mg, 0.046 mmol), tert-butyl 3-[4-(benzyloxy)-3-iodo-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate (25 mg, 0.046 mmol) and DMSO (460 μL). The mixture was sparged with nitrogen for 2 minutes and then cyclopropylamine (22 μL, 0.32 mmol) was added. The mixture was sparged with nitrogen for an additional 2 minutes and then the vial was sealed and heated to 80° C. for 2 hours. The reaction was cooled to room temperature, diluted with EtOAc, and the organic layers were washed with water, brine, and dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the residue by silica chromatography, eluting with 0-100% EtOAc in hexanes followed by further purification by preparatory thin layer chromatography (PTLC) with 2% MeOH/CH₂Cl₂ (3 elutions) afforded compound 3b. LRMS (ESI) calc'd for C₂₆H₃₁N₆O₃ [M+H]⁺: 475. found 475. ¹H NMR (600 MHz, CDCl₃): δ 7.82 (d, J=6.0 Hz, 1H), 7.42 (d, J=7.2 Hz, 2H), 7.38 (t, J=7.2 Hz, 2H), 7.33 (t, J=7.2 Hz, 1H), 6.64 (d, J=6.0 Hz, 1H), 5.51 (s, 2H), 5.06 (s, 1H), 4.65 (d, J=9.6 Hz, 2H), 4.26 (d, J=9.0 Hz, 2H), 3.08 (s, 2H), 2.63 (m, 1H), 1.45 (s, 9H), 0.71 (m, 2H), 0.51 (m, 2H).

Step 3: tert-butyl 3-(cyanomethyl)-3-[3-(cyclopropylamino)-4-oxo-4,5-dihydro-1H-pyrazolo-[4,3-c]pyridin-1-yl]azetidine-1-carboxylate

To a solution of tert-butyl 3-[4-(benzyloxy)-3-(cyclopropylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl]-3-(cyanomethyl)azetidine-1-carboxylate (3.0 mg, 0.0063 mmol) in EtOAc (1 mL) was added 10% Pd/C (5 mg). The reaction was stirred under 1 atmosphere of hydrogen at room temperature for 2 hours. The balloon of hydrogen was removed and the reaction was filtered through Celite (washing with DCM) and the filtrate concentrated in vacuo. The residue was purified by preparatory thin layer chromatography (PTLC) with 4% MeOH/CH₂Cl₂ to afford compound 3. LRMS (ESI) calc'd for C₁₉H₂₅N₆O₃ [M+H]⁺: 385. found 385. ¹H NMR (600 MHz, DMSO-d6): δ 10.98 (d, J=6.0 Hz, 1H), 7.09 (dd, J=7.2, 6.0 Hz, 1H), 6.20 (d, J=7.2 Hz, 1H), 5.67 (d, J=2.4 Hz, 1H), 4.41 (m, 2H), 4.19 (m, 2H), 3.29 (s, 2H), 2.54 (m, 1H), 1.36 (s, 9H), 0.59 (m, 2H), 0.48 (m, 2H).

Example 4-1 tert-butyl 3-(cyanomethyl)-3-(4-oxo-3-((2-(trifluoromethyl)pyridin-4-yl)amino)-4,5-dihydro-1H-pyrazolo[43-c]pyridin-1-yl)azetidine-1-carboxylate

To a vial was charged with tert-butyl 3-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (35 mg, 0.10 mmol), 4-bromo-2-trifluoromethyl pyridine (34.5 mg, 0.152 mmol), Pd₂(dba)₃ (4.65 mg, 5.08 gmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.020 mmol), and Cs₂CO₃ (66.2 mg, 0.203 mmol). Dioxane (0.68 mL) was added and the mixture was purged with argon for 5 minutes. The vial was then sealed and heated at 90° C. for 3 hours. The mixture was cooled and filtered through Celite with 3:1 CHCl₃:IPA and the resulting solution was concentrated in vacuo. The residue was taken up in DMSO and purified by mass triggered reverse phase HPLC, eluting with acetonitrile/water containing 0.1% TFA modifier. Fractions containing desired product were diluted with EtOAc, washed with saturated aqueous NaHCO₃, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford compound 4-1. LRMS (ESI) calc'd for C₂₂H₂₃F₃N₇O₃ [M+H]⁺: 490. found 490. ¹H NMR (600 MHz, DMSO-d6): δ 11.36 (s, 1H), 9.20 (s, 1H), 8.42 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 7.87 (m, 1H), 7.25 (m, 1H), 6.40 (d, J=7.2 Hz, 1H), 4.47 (m, 2H), 4.27 (d, J=8.4 Hz, 2H), 3.45 (s, 2H), 1.36 (s, 9H).

The following Examples in Table 19 were prepared in analogy to Example 4-1:

TABLE 19 Example Structure Compound Name LRMS 4-2

tert-butyl 3-(cyanomethyl)- 3-(3((4(methoxycarbonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)azetidine- 1-carboxylate LRMS (ESI) calc'd for C₂₄H₂₇N₆O₅ [M + H]⁺: 479, found 479. 4-3

tert-butyl 3-(cyanomethyl)- 3-(3-((4- fluorophenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)azetidine-1-carboxylate LRMS (ESI) calc'd for C₂₂H₂₄FN₆O₃ [M + H]⁺: 439, found 439.

Example 5-1 tert-butyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

Step 1: tert-butyl 4-(4-(benzyloxy)-3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

To tert-butyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (3.00 g, 6.49 mmol), 4-bromo-N,N-dimethylbenzenesulfonamide (3.43 g, 13.0 mmol), Pd₂dba₃ (0.594 g, 0.649 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.935 g, 1.95 mmol) and potassium phosphate tribasic (2.75 g, 13.0 mmol) in a degassed sealed microwave vial, was added t-amyl alcohol (86 mL) and the reaction was degassed again by evacuation/argon backfill (×3) and heated to 75° C. overnight. The reaction was concentrated and purified by silica chromatography, eluting with 10-80% EtOAc in hexanes. The desired product, 5-la, was collected and concentrated in vacuo to afford the desired product as a solid. LRMS (ESI) calc'd for C₃₃H₄₀N₇O₅S [M+H]: 646. found 646. ¹H NMR (600 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.85 (d, J=6.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.46 (d, J=7.8 Hz, 2H), 7.35 (m, 3H), 7.28 (m, 1H), 5.57 (s, 2H), 3.75 (d, J=14.4 Hz, 2H), 3.28 (s, 2H), 3.03 (br s, 2H), 2.74 (d, J=14.4 Hz, 2H), 2.47 (s, 6H), 2.03 (t, J=10.8 Hz, 2H), 1.37 (s, 9H).

Step 2: tert-butyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamol)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

To tert-butyl 4-(4-(benzyloxy)-3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (3.37 g, 5.22 mmol) was added Pd/C (10 wt % Pd loading, 0.27 g) and ethyl acetate (26 mL). The suspension was then evacuated and backfilled with hydrogen and the reaction was stirred under hydrogen at 1 atmosphere overnight at room temperature. The reaction was filtered through Celite and the filter pad was washed with DCM and the organic solvents were concentrated in vacuo. The solid was purified by silica chromatography, eluting with 0-6% methanol in DCM to afford 5-1, as a green solid that was triturated from DCM to afford analytically pure solid. LRMS (ESI) calc'd for C₂₁H₂₆N₇O₃S [M-Boc+H]⁺: 456. found 456. ¹H NMR (600 MHz, DMSO-d6): δ 11.33 (s, 1H), 8.68 (s, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.17 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 3.70 (d, J=13.8 Hz, 2H), 3.24 (s, 6H), 3.05 (br s, 2H), 2.64 (d, J=13.8 Hz, 2H), 2.45 (s, 6H), 1.99 (apparent t, J=12.0 Hz, 2H), 1.35 (s, 9H).

The following examples outlined in Table 20 were prepared by analogy using the general procedure outlined above for Example 5-1. In select cases, the general procedure could be modified to alternatively utilize KOAc base, 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl ligand instead, [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (t-BuXPhos Pd G3) precatalyst in place of the individual phosphine and palladium source, and/or 2-propanol in place of t-amyl alcohol. Additionally, in certain instances the cross coupling could be run between 70-90° C. thermally, or at 105° C. in a microwave. In certain instances, the general procedure for the hydrogenolysis could be modified to employ a suitable alternate solvent (such as MeOH, EtOH etc.) or cosolvent thereof with EtOAc to ensure dissolution of the substrate. In certain other instances, such as for Examples 5-224 to 5-226, removal of the Bn protecting group could alternatively be achieved via hydrolysis in 1,4-dioxane (0.04 M) using concentrated aqueous HCl (˜2:1 ratio by volume of 1,4-dioxane:conc. HCl) or via saturated HCl in ethyl acetate at room temperature (as done for Examples 5-271, 5-272, 5-277 and 5-278 for instance).

TABLE 20 Example Structure Compound Name LRMS 5-2

tert-butyl 4-(cyanomethyl)- 4-[4-oxo-3-({4-[(1S or 1R)- 2,2,2-trifluoro-1- hydroxyethyl]phenyl} amino)-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl]piperidine- 1-carboxylate Chiral separation on free pyridone using SFC, Chiralpak IA, 29% MeOH in CO₂ Tr = 4.4 minutes. LRMS (ESI) calc'd for C₂₆H₃₀N₆O₄F₃ [M + H]⁺: 547, found 547. 5-3

tert-butyl 4-(cyanomethyl)- 4-[4-oxo-3-({4-[(1R or 1S)- 2,2,2-trifluoro-1- hydroxyethyl]phenyl} amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl]piperidine-1- carboxylate Chiral separation on free pyridone using SFC, Chiralpak IA, 29% MeOH in CO₂ Tr = 3.7 minutes. LRMS (ESI) calc'd for C₂₆H₃₀N₆O₄F₃ [M + H]⁺: 547, found 547. 5-4

tert-butyl 4-(cyanomethyl)- 4-{4-oxo-3-[(4- sulfamoylphenyl)amino]- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₄H₃₀N₇O₅S [M + H]⁺: 528, found 528. 5-5

tert-butyl 4-(cyanomethyl)- 4-(4-oxo-3-{[1-oxo-2- (2,2,2-trifluoroethyl)-2,3- dihydro-1H-isoindol-5- yl]amino}-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₈H₃₁N₇O₄F₃ [M + H]⁺: 586, found 586. 5-6

tert-butyl 4-(cyanomethyl)- 4-{3-[(2-methyl-1,1- dioxido-2,3-dihydro-1,2- benzisothiazol-5-yl) amino]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl}piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₁H₂₄N₇O₃S [M − Boc + H]⁺: 454, found 454. 5-7

tert-butyl 4-(cyanomethyl)- 4-(4-oxo-3-{[4- (pentafluorosulfanyl) phenyl]amino}-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) piperidine-1-carboxylate LRMS (ESI) calc'd for C₁₉H₂₀N₆OSF₅ [M − Boc + H]⁺: 475, found 475. 5-8

tert-butyl 4-(cyanomethyl)- 4-(4-oxo-3-{[4- (trifluoromethyl) phenyl]amino}-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₅H₂₈N₆O₃F₃ [M + H]⁺: 517, found 517. 5-9

tert-butyl (3R,4R)-4- (cyanomethyl)-3-fluoro-4- {3-[(2-methyl-1,1-dioxido- 2,3-dihydro-1,2- benzisothiazol-5-yl) amino]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl}piperidine- 1-carboxylate (from I-6-2B) LRMS (ESI) calc'd for C₂₁H₂₃N₇O₃FS [M − Boc + H]⁺: 472, found 472. 5-10

tert-butyl (3R,4S and 3S,4R)- 4-(cyanomethyl)-3-methyl- 4-(3-{[4-(methylsulfonyl) phenyl]amino}-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₃N₆O₅S [M + H]⁺: 541, found 541. 5-11

tert-butyl (3S,4S and 3R,4R)- 4-(cyanomethyl)-3-methyl- 4-(3-{[4- (methylsulfonyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₆H₃₃N₆O₅S [M + H]⁺: 541, found 541. 5-12

tert-butyl 4-(cyanomethyl)- 4-(4-oxo-3-((1-oxo-2,3- dihydro-1H-inden-5-yl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₇H₃₁N₆O₄ [M + H]⁺: 503, found 503. 5-13

tert-butyl 4-(cyanomethyl)- 4-(3-{[3- (methylsulfonyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₅H₃₁N₆O₅S [M + H]⁺: 527, found 527. 5-14

tert-butyl (3S,4R or 3R,4S)- 4-(cyanomethyl)-3-fluoro- 4-(3-{[4- (methylsulfonyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate (from I-7-1A) LRMS (ESI) calc'd for C₂₅H₃₀FN₆O₅S [M + H]⁺: 545, found 545. 5-15

tert-butyl (3R,4S or 3S,4R)- 4-(cyanomethyl)-3-fluoro- 4-(3-{[4- (methylsulfonyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate (from I-7-1B) LRMS (ESI) calc'd for C₂₅H₃₀FN₆O₅S [M + H]⁺: 545, found 545. 5-16

tert-butyl (3S,4S)-4- (cyanomethyl)-3-fluoro- 4-(3-{[4-(methyl- sulfonyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate (from I-7-2A) LRMS (ESI) calc'd for C₂₅H₃₀FN₆O₅S [M + H]⁺: 545, found 545. 5-17

tert-butyl (3R,4R)-4- (cyanomethyl)-3-fluoro- 4-(3-{[4-(methylsulfonyl) phenyl]amino}-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) piperidine-1-carboxylate (from I-7-2B) LRMS (ESI) calc'd for C₂₅H₃₀FN₆O₅S [M + H]⁺: 545, found 545. 5-18

tert-butyl (3R,4R)-4- (cyanomethyl)-4-(3-{[4- (dimethylsulfamoyl) phenyl]amino}-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl)-3- fluoropiperidine-1- carboxylate (from I-7-2B) LRMS (ESI) calc'd for C₂₆H₃₃FN₇O₅S [M + H]⁺: 574, found 574. 5-19

tert-butyl (3R,4R)-4- (cyanomethyl)-3-fluoro- 4-[4-oxo-3-(phenyl- amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl]piperidine-1- carboxylate (from I-7-2B) LRMS (ESI) calc'd for C₂₄H₂₈FN₆O₃ [M + H]⁺: 467, found 467. 5-20

tert-butyl (3R,4R)-4- (cyanomethyl)-3-fluoro-4- [4-oxo-3-({4-[(1S or 1R)- 2,2,2-trifluoro-1- hydroxyethyl] phenyl}amino)-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl] piperidine-1-carboxylate (from I-7-2B & I-25B) LRMS (ESI) calc'd for C₂₆H₂₉F₄N₆O₄ [M + H]⁺: 565, found 565. 5-21

tert-butyl (3R,4R)-4- (cyanomethyl)-3-fluoro-4- [4-oxo-3-({4-[(1R or 1S)- 2,2,2-trifluoro-1- hydroxyethyl]phenyl} amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]piperidine-1-carboxylate (from I-7-2B & I-25A) LRMS (ESI) calc'd for C₂₆H₂₉F₄N₆O₄ [M + H]⁺: 565, found 565. 5-22

tert-butyl (3R,4R)-4-{3- [(2-tert-butyl-1,1-dioxido- 2,3-dihydro-1,2- benzisothiazol-5-yl) amino]-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl}-4- (cyanomethyl)-3- fluoropiperidine-1- carboxylate (from I-7-2B) LRMS (ESI) calc'd for C₂₉H₃₇FN₇O₅S [M + H]⁺: 614, found 614. 5-23

tert-butyl 4-{3-[(2-tert- butyl-1,1-dioxido-2,3- dihydro-1,2- benzisothiazol-5-yl) amino]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl}-4- (cyanomethyl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₉H₃₈N₇O₅S [M + H]⁺: 596, found 596. 5-24

tert-butyl (3R,4R)-4- (cyanomethyl)-4-(3-{[1,1- dioxido-2-(2,2,2- trifluoroethyl)-2,3-dihydro- 1,2-benzisothiazol-5- yl]amino}-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-3- fluoropiperidine-1- carboxylate (from I-7-2B) LRMS (ESI) calc'd for C₂₇H₃₀F₄N₇O₅S [M + H]⁺: 640, found 640. 5-25

tert-butyl 4-(cyanomethyl)- 4-(3-((1,1-dioxido-2-(2,2,2- trifluoroethyl)-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₇H₃₁F₃N₇O₅S [M + H]⁺: 622, found 622. 5-26

2-(4-(3-((2-(tert-butyl)-1,1- dioxido-2,3-dihydrobenzo [d]isothiazol-5-yl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-1-(2,2-difluoro- propanoyl)piperidin-4-yl) acetonitrile LRMS (ESI) calc'd for C₂₇H₃₂F₂N₇O₄S [M + H]⁺: 588, found 588. 5-27

(S)-2-(3-(4-oxo-3- (phenylamino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B) LRMS (ESI) calc'd for C₁₉H₂₀N₅O₂ [M + H]⁺: 350, found 350. 5-28

(S)-4-((1-(3-(cyanomethyl) tetrahydro-2H-pyran-3-yl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N,N-dimethyl benzenesulfonamide (from I-17B) LRMS (ESI) calc'd for C₂₁H₂₅N₆O₄S [M + H]⁺: 457, found 457. 5-29

(R)-4-((1-(3-(cyanomethyl) tetrahydro-2H-pyran-3-yl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N,N-dimethyl benzenesulfonamide (from I-17A) LRMS (ESI) calc'd for C₂₁H₂₅N₆O₄S [M + H]⁺: 457, found 457. 5-30

(R)-2-(3-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 3-yl)acetonitrile (from I-17A) LRMS (ESI) calc'd for C₂₀H₂₂N₅O₄S [M + H]⁺: 428, found 428. 5-31

(S)-2-(3-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₀H₂₂N₅O₄S [M + H]⁺: 428, found 428. 5-32

(2S,5S and 2R,5R)-methyl 5-(cyanomethyl)-5-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (racemic mixture) LRMS (ESI) calc'd for C₂₂H₂₄N₅O₆S [M + H]⁺: 486, found 486. 5-33

(2S,5S or 2R,5R)-methyl 5-(cyanomethyl)-5-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate Chiral separation on free pyridone using SFC, AD-H column, 35% MeOH in CO₂ Tr = 5.9 minutes. LRMS (ESI) calc'd for C₂₂H₂₄N₅O₆S [M + H]⁺: 486, found 486. 5-34

(2S,5S or 2R,5R)-methyl 5-(cyanomethyl)-5-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate Chiral separation on free pyridone using SFC, AD-H column, 35% MeOH in CO₂ TR = 7.5 minutes. LRMS (ESI) calc'd for C₂₂H₂₄N₅O₆S [M + H]⁺: 486, found 486. 5-35

(2R,5S and 2S,5R)-tert- butyl 5-(cyanomethyl)-5- (3-((4-(methylsulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H-pyran-2- carboxylate (from racemic I-14-2) LRMS (ESI) calc'd for C₂₅H₃₀N₅O₆S [M + H]⁺: 528, found 528. 5-36

(2S,5S and 2R,5R)-tert-butyl 5-(cyanomethyl)-5-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran-2- carboxylate (from racemic I-14-1) LRMS (ESI) calc'd for C₂₅H₃₀N₅O₆S [M + H]⁺: 528, found 528. 5-37

(2R,5S or 2S,5R)-tert-butyl 5-(cyanomethyl)-5-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (from Example 5-35) Chiral separation of free pyridone using SFC, AD-H column, 25% MeOH in CO₂ Tr = 3.8 minutes. LRMS (ESI) calc'd for C₂₅H₃₀N₅O₆S [M + H]⁺: 528, found 528. 5-38

tert-butyl 4-(cyanomethyl)- 4-(4-oxo-3-((4-(((2,2,2- trifluoroethyl)amino)methyl) phenyl)amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₅H₂₉N₆O₃ [M − NHCH₂CF₃]⁺: 461, found 461. 5-39

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (from Example 5-36) Chiral separation of free pyridone using LC column, IB column, 40% MeOH/EtOH = 3:2, 60% heptanes, Tr = 8.1 minutes. LRMS (ESI) calc'd for C₂₅H₃₀N₅O₆S [M + H]⁺: 528, found 528. 5-40

(2R,5R)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (methylsulfonyl)phenyl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H-pyran-2- carboxylate (from Example 5-36) Chiral separation of free pyridone using LC column, IB column, 40% MeOH/EtOH = 3:2, 60% heptanes, Tr = 9.6 minutes. LRMS (ESI) calc'd for C₂₅H₃₀N₅O₆S [M + H]⁺: 528, found 528. 5-41

(2S,5S)-tert-butyl 5-(3- ((2-(tert-butyl)-1,1- dioxido-2,3-dihydrobenzo [d]isothiazol-5-yl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-5-(cyanomethyl) tetrahydro-2H-pyran-2- carboxylate (from I- 14-1A) LRMS (ESI) calc'd for C₂₉H₃₇N₆O₆S [M + H]⁺: 597, found 597. 5-42

(2R,5R)-tert-butyl 5-(3-((2- (tert-butyl)-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1B) LRMS (ESI) calc'd for C₂₉H₃₇N₆O₆S [M + H]⁺: 597, found 597. 5-43

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (N,N- dimethylsulfamoyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₆H₃₃N₆O₆S [M + H]⁺: 557, found 557. 5-44

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((1,1- dioxido-2-(2,2,2- trifluoroethyl)-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₀F₃N₆O₆S [M + H]⁺: 623, found 623. 5-45

tert-butyl 3-(cyanomethyl)- 3-(3-{[4-(methylsulfonyl) phenyl]amino}-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)azetidine-1- carboxylate LRMS (ESI) calc'd for C₁₈H₁₉N₆O₃S [M − Boc + H]⁺: 399, found 399. 5-46

tert-butyl 3-(cyanomethyl)- 3-{3-[(2-fluoropyridin-4- yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl}azetidine- 1-carboxylate LRMS (ESI) calc'd for C₂₁H₂₃FN₇O₃ [M + H]⁺: 440, found 440. 5-47

tert-butyl 3-(cyanomethyl)- 3-[4-oxo-3-({4- [(trifluoromethyl)sulfonyl] phenyl}amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl]azetidine-1-carboxylate LRMS (ESI) calc'd for C₂₃H₂₄F₃N₆O₅S [M + H]⁺: 553, found 553. 5-48

tert-butyl 4-(cyanomethyl)- 4-{3-[(4-fluorophenyl) amino]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl}piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₄H₂₈FN₆O₃ [M + H]⁺: 467, found 467. 5-49

tert-butyl 4-(cyanomethyl)- 4-(3-((4-(N,N- dimethylsulfamoyl)-3- methylphenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₂H₂₈N₇O₃S [M − Boc + H]⁺: 470, found 470. 5-50

(2R,5S)-tert-butyl 5-(3-((4- ((R or S)-1-amino-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)-5-(cyanomethyl) tetrahydro-2H-pyran-2- carboxylate (from epimerized I-14-1A & I-29A) LRMS (ESI) calc'd for C₂₆H₃₀F₃N₆O₄ [M + H]⁺: 547, found 547. 5-51

(2S,5S)-tert-butyl 5-(3-((4- ((R or S)-1-amino-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl)- 5-(cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A & I-29A) LRMS (ESI) calc'd for C₂₆H₃₀F₃N₆O₄ [M + H]⁺: 547, found 547. 5-52

(2R,5S)-tert-butyl 5-(3-((4- ((S or R)-1-amino-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)-5-(cyanomethyl) tetrahydro-2H-pyran-2- carboxylate (from epimerized I-14-1A & I-29B) LRMS (ESI) calc'd for C₂₆H₃₀F₃N₆O₄ [M + H]⁺: 547, found 547. 5-53

(2S,5S)-tert-butyl 5-(3-((4- ((S or R)-1-amino-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl)-5- (cyanomethyl) tetrahydro-2H-pyran-2- carboxylate (from I-14-1A & I-29B) LRMS (ESI) calc'd for C₂₆H₃₀F₃N₆O₄ [M + H]⁺: 547, found 547. 5-54

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- (phenylamino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₄H₂₈N₅O₄ [M + H]⁺: 450, found 450. 5-55

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- methyl-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₆H₃₁N₆O₆S [M + H]⁺: 555, found 555. 5-56

N-(tert-butyl)-4-((1-(4- (cyanomethyl)-1-(2,2- difluoropropanoyl)piperidin- 4-yl)-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)benzene- sulfonamide LRMS (ESI) calc'd for C₂₆H₃₂F₂N₇O₄S [M + H]⁺: 576, found 576. 5-57

2-(1-(2,2- difluoropropanoyl)-4-(3- ((4-(isopropylsulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidin-4- yl)acetonitrile LRMS (ESI) calc'd for C₂₅H₂₉F₂N₆O₄S [M + H]⁺: 547, found 547. 5-58

N-(tert-butyl)-4-((1-(4- (cyanomethyl)-1-(2,2- difluoropropanoyl)piperidin- 4-yl)-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N- methylbenzenesulfonamide LRMS (ESI) calc'd for C₂₇H₃₃F₂N₇O₄SNa [M + Na]⁺: 612, found 612. 5-59

2-(4-(3-((4-(tert- butylsulfonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-1-(2,2-difluoro- propanoyl)piperidin-4- yl)acetonitrile LRMS (ESI) calc'd for C₂₆H₃₀F₂N₆O₄S [M + H]⁺: 561, found 561. 5-60

tert-butyl 4-(3-(3,5-bis((1H- pyrazol-1-yl)methyl)phenyl amino)-4-oxo-4,5-dihydro pyrazolo[4,3-c]pyridin-1-yl)- 4-(cyanomethyl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₂H₃₇N₁₀O₃ [M + H]⁺: 609, found 609. 5-61

tert-butyl 4-(cyanomethyl)- 4-(3-(3,5- dimethylphenylamino)-4- oxo-4,5- dihydropyrazolo[4,3-c] pyridin-1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₆H₃₃N₆O₃ [M + H]⁺: 477, found 477. 5-62

tert-butyl 4-(3-(3,5-bis((1H- 1,2,3-triazol-1-yl)methyl) phenylamino)-4-oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₃₀H₃₅N₁₂O₃ [M + H]⁺: 611, found 611. 5-63

tert-butyl 4-(3-(3,5-bis((2H- 1,2,3-triazol-2-yl)methyl) phenylamino)-4-oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₃₀H₃₅N₁₂O₃ [M + H]⁺: 611, found 611 5-64

tert-butyl 4-(3-(3-((1H- 1,2,3-triazol-1-yl)methyl)- 5-((2H-1,2,3-triazol-2-yl) methyl)phenylamino)-4- oxo-4,5-dihydropyrazolo [4,3-c]pyridin-1-yl)-4- (cyanomethyl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₀H₃₅N₁₂O₃ [M + H]⁺: 611, found 611. 5-65

tert-butyl 4-(3-(m- toluidino)-4-oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)-4- (cyanomethyl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₅H₃₁N₆O₃ [M + H]⁺: 463, found 463. 5-66

tert-butyl 4-(cyanomethyl)- 4-(3-(isoindolin-5-ylamino)- 4-oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₂N₇O₃ [M + H]⁺: 490, found 490. 5-67

1,1-dioxo-2,3-dihydro-1,2- benzothiazol-5-yl]amino}- 4-oxo-1H,4H,5H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₉H₃₈N₇O₅S [M + H]⁺: 596, found 596. 5-68

tert-butyl 4-(cyanomethyl)- 4-(3-{[2- (cyclopropylmethyl)-1,1- dioxo-2,3-dihydro-1,2- benzothiazol-5-yl]amino}- 4-oxo-1H,4H,5H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate MS (ESI) calc'd for C₂₉H₃₆N₇O₅S [M + H]⁺: 594, found 594. 5-69

tert-butyl 4-(cyanomethyl)- 4-{3-[(2-ethyl-1,1-dioxo- 2,3-dihydro-1,2- benzothiazol-5-yl)amino]-4- oxo-1H,4H,5H-pyrazolo[4,3- c]pyridin-1-yl}piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₂H₂₆N₇O₃S [M − Boc + H]⁺: 468, found 468. 5-70

methyl 4-(cyanomethyl)-4- [3-[(2-methyl-1,1-dioxo-2,3- dihydro-1,2-benzothiazol-5- yl)amino]-4-oxo-1H,4H,5H- pyrazolo[4,3-c]pyridin-1- yl]piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₃H₂₆N₇O₅S [M + H]⁺: 512, found 512. 5-71

methyl 4-{3-[(2-tert-butyl- 1,1-dioxo-2,3-dihydro-1,2- benzothiazol-5-yl)amino]- 4-oxo-1H,4H,5H-pyrazolo [4,3-c]pyridin-1-yl}-4- (cyanomethyl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₂N₇O₅S [M + H]⁺: 554, found 554. 5-72

methyl 4-{3-[(2-ethyl-1,1- dioxo-2,3-dihydro-1,2- benzothiazol-5-yl)amino]-4- oxo-1H,4H,5H-pyrazolo [4,3-c]pyridin-1-yl}-4- (cyanomethyl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₄H₂₈N₇O₅S [M + H]⁺: 526, found 526. 5-73

methyl 4-(cyanomethyl)-4- (3-{[2-(2-methylpropyl)-1,1- dioxo-2,3-dihydro-1,2- benzothiazol-5-yl]amino}- 4-oxo-1H,4H,5H-pyrazolo [4,3-c]pyridin-1-yl) piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₂N₇O₅S [M + H]⁺: 554, found 554. 5-74

methyl 4-(cyanomethyl)-4- (3-{[2-(cyclopropylmethyl)- 1,1-dioxo-2,3-dihydro-1,2- benzothiazol-5-yl]amino}- 4-oxo-1H,4H,5H-pyrazolo [4,3-c]pyridin-1-yl) piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₀N₇O₅S [M + H]⁺: 552, found 552. 5-75

methyl 4-(cyanomethyl)-4- (3-{[2-(cyclopentylmethyl)- 1,1-dioxo-2,3-dihydro-1,2- benzothiazol-5-yl]amino}- 4-oxo-1H,4H,5H-pyrazolo [4,3-c]pyridin-1-yl) piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₈H₃₄N₇O₅S [M + H]⁺: 580, found 580. 5-76

tert-butyl 4-(cyanomethyl)- 4-[4-oxo-3-({4- [(trifluoromethyl) sulfonyl]phenyl}amino)- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl] piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₅H₂₈F₃N₆O₅S [M + H]⁺: 581, found 525. 5-77

tert-butyl 4-(cyanomethyl)- 4-(3-{[4- (methylsulfonyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₀H₂₃N₆O₃S [M − Boc + H]⁺: 427, found 427. 5-78

tert-butyl 4-(cyanomethyl)- 4-{3-[(2-fluoropyridin-4- yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl}piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₃H₂₇FN₇O₃ [M + H]⁺: 468, found 468. 5-79

4-(1-(1-(cyanomethyl) cyclohexyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-ylamino)-N,N- dimethylbenzene- sulfonamide LRMS (ESI) calc'd for C₂₂H₂₇N₆O₃S [M + H]⁺: 455, found 455. 5-80

2-(1-(3-((2-(tert-butyl)-1,1- dioxido-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₅H₃₁N₆O₃S [M + H]⁺: 495, found 495. 5-81

2-(1-(3-((2-methyl-1,1- dioxido-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₂H₂₅N₆O₃S [M + H]⁺: 453, found 453. 5-82

tert-butyl 4-(cyanomethyl)- 4-(3-((1,1-dioxido-2,3- dihydrobenzo[d]thiophen- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₁N₆O₅S [M + H]⁺: 539, found 539. 5-83

2-(8-(4-oxo-3-((4- (trifluoromethyl)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-1,4-dioxaspiro[4.5] decan-8-yl)acetonitrile LRMS (ESI) calc'd for C₃₀H₂₈F₃N₅O₃ [M + H]⁺: 474, found 474. 5-84

4-({1-[(1R,2R))-1- (cyanomethyl)-2- fluorocyclohexyl]-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-3-yl} amino)-N,N- dimethylbenzene- sulfonamide (from I-19A) LRMS (ESI) calc'd for C₂₂H₂₆N₆O₃FS [M + H]⁺: 473, found 473. 5-85

{(1R,2R)-2-fluoro-1-[4- oxo-3-({4-[(1S or 1R)-2,2,2- trifluoro-1-hydroxy-1- methylethyl]phenyl} amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]cyclohexyl}acetonitrile (derived from aryl bromide I-32A and I-19A) LRMS (ESI) calc'd for C₂₃H₂₄F₄N₅O₂ [M + H]⁺: 478, found 478. 5-86

{(1R,2R)-2-fluoro-1-[4- oxo-3-({4-[(1R or 1S)- 2,2,2-trifluoro-1-hydroxy- 1-methylethyl]phenyl} amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]cyclohexyl}acetonitrile (derived from aryl bromide I-32B and I-19A) LRMS (ESI) calc'd for C₂₃H₂₄F₄N₅O₂ [M + H]⁺: 478, found 478. 5-87

{(1R,2R)-2-fluoro-1-[3- ({4-[(1-methylethyl) sulfonyl]phenyl} amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl]cyclohexyl}acetonitrile (from I-19A) LRMS (ESI) calc'd for C₂₃H₂₇N₅O₃F [M + H]⁺: 472, found 472. 5-88

(R or S)-2-(1-(3-((4-(1- amino-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)cyclopentyl)acetonitrile (derived from aryl bromide I-29A) LRMS (ESI) calc'd for C₂₁H₂₂N₆OF₃ [M + H]⁺: 431, found 431. 5-89

(R or S)-2-(1-(3-((4-(1- amino-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)cyclopentyl)acetonitrile (derived from aryl bromide I-29B) LRMS (ESI) calc'd for C₂₁H₂₂N₆OF₃ [M + H]⁺: 431, found 431. 5-90

(2S,5S)-tert-butyl 5-(3-((4- (N-(tert-butyl)-N- methylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₉H₃₉N₆O₆S [M + H]⁺: 599, found 599. 5-91

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4-(N- isopropyl-N- methylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₃₇N₆O₆S [M + H]⁺: 585, found 585. 5-92

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4-(N- ethyl-N-methylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₅N₆O₆S [M + H]⁺: 571, found 571. 5-93

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((1,1- dioxido-2-(2,2,2- trifluoroethyl)-2,3- dihydrobenzo[d]isothiazol- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₀N₆O₆F₃S [M + H]⁺: 623, found 623. 5-94

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4-(N- methylsulfamoyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₆H₃₁N₆O₆S [M + H]⁺: 543, found 543. 5-95

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4- oxo-3-((1-oxo-2-(2,2,2- trifluoroethyl)isoindolin-5- yl)amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₃₀N₆O₅F₃ [M + H]⁺: 587, found 587. 5-96

(2S,5S)-tert-butyl 5-(3-((4- ((1H-1,2,3-triazol-1- yl)methyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-5-(cyanomethyl) tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₁N₈O₄ [M + H]⁺: 531, found 531. 5-97

(2S,5S)-tert-butyl 5-(3-((4- ((2H-1,2,3-triazol-2- yl)methyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-5-(cyanomethyl) tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₁N₈O₄ [M + H]⁺: 531, found 531. 5-98

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (isopropylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₄N₅O₆S [M + H]⁺: 556, found 556. 5-99

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (cyclopropylsulfonyl) phenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₂N₅O₆S [M + H]⁺: 554, found 554. 5-100

(2S,5S)-tert-butyl 5-(3-((2- (tert-butyl)-1- oxoisoindolin-5-yl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₀H₃₇N₆O₅ [M + H]⁺: 561, found 561. 5-101

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- cyclohexyl-1- oxoisoindolin-5-yl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₂H₃₉N₆O₅ [M + H]⁺: 587, found 587. 5-102

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- cyclopentyl-1- oxoisoindolin-5-yl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₁H₃₇N₆O₅ [M + H]⁺: 573, found 573. 5-103

(2S,5S)-tert-butyl 5-(3- ((4-(1-amino-2,2,2- trifluoroethyl) phenyl)amino)-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c] pyridin-1-yl)-5- (cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (derived from aryl bromide I-29A and I-14-1A) LRMS (ESI) calc'd for C₂₆H₃₀N₆O₄F₃ [M + H]⁺: 547, found 547. 5-104

(2S,5S)-tert-butyl 5-(3- ((4-(1-amino-2,2,2- trifluoroethyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (derived from aryl bromide I-29B and I-14-1A) LRMS (ESI) calc'd for C₂₆H₃₀N₆O₄F₃ [M + H]⁺: 547, found 547. 5-105

[(3S)-3-(3-{[4-(azetidin-1- ylsulfonyl)phenyl]amino}- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₂H₂₅N₆O₄S [M + H]⁺: 469, found 469. 5-106

{(3S)-3-[3-({4-[(3- methylazetidin-1-yl) sulfonyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl}acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₃H₂₇N₆O₄S [M + H]⁺: 483, found 483. 5-107

{(3S)-3-[3-({4-[(2,2- dimethylpyrrolidin-1- yl)sulfonyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl} acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₅H₃₁N₆O₄S [M + H]⁺: 511, found 511. 5-108

[(3S)-3-{3-[(4-{[(2R or 2S)- 2-methylazetidin-1- yl]sulfonyl}phenyl)amino]- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydro-2H-pyran-3- yl]acetonitrile (derived from aryl bromide I-20-17A and I- 17B) LRMS (ESI) calc'd for C₂₃H₂₇N₆O₄S [M + H]⁺: 483, found 483. 5-109

[(3S)-3-{3-[(4-{[(2S or 2R)- 2-methylazetidin-1- yl]sulfonyl}phenyl)amino]- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydro-2H-pyran-3- yl]acetonitrile (derived from aryl bromide I-20-17B and I-17B) LRMS (ESI) calc'd for C₂₃H₂₇N₆O₄S [M + H]⁺: 483, found 483. 5-110

{(3S)-3-[4-oxo-3-({4-[(1S or 1R)-2,2,2-trifluoro-1- hydroxy-1- methylethyl]phenyl} amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl]tetrahydro-2H-pyran- 3-yl}acetonitrile (derived from aryl bromide I-32A and I-17B) LRMS (ESI) calc'd for C₂₂H₂₃N₅O₃F₃ [M + H]⁺: 462, found 462. 5-111

{(3S)-3-[4-oxo-3-({4-[(1R or 1S)-2,2,2-trifluoro-1- hydroxy-1- methylethyl]phenyl} amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]tetrahydro-2H-pyran-3- yl}acetonitrile (derived from aryl bromide I-32B and I-17B) LRMS (ESI) calc'd for C₂₂H₂₃N₅O₃F₃ [M + H]⁺: 462, found 462. 5-112

(S or R)-ethyl 3-(4-((1- ((3S)-3-(cyanomethyl) tetrahydro-2H-pyran-3- yl)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-3-yl)amino) phenyl)-4,4,4-trifluoro- 3-hydroxy-2,2- dimethylbutanoate (from I-17B, derived from Peak I via SFC on free pyridone: Chiralpak IC, 25% MeOH in CO₂, Tr = 6.2 minutes) LCMS (ESI) Calc'd for C₂₇H₃₁F₃N₅O₅ [M + H]⁺: 562, found 562. 5-113

(S or R)-ethyl 3-(4-((1- ((3S)-3-(cyanomethyl) tetrahydro-2H-pyran-3- yl)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-3-yl)amino) phenyl)-4,4,4- trifluoro-3-hydroxy-2,2- dimethylbutanoate (from I- 17B, derived from Peak 2 via SFC on free pyridone: Chiralpak IC, 25% MeOH in CO₂, Tr = 7.9 minutes) LCMS (ESI) Calc'd for C₂₇H₃₁F₃N₅O₅ [M + H]⁺: 562, found 562. 5-114

2-((S)-3-(3-((4-((S or R)- 3-hydroxy-3- (trifluoromethyl) pyrrolidine-1-carbonyl)- 3-methylphenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B and I-39-2A.) LCMS (ESI) Calc'd for C₂₆H₂₈F₃N₆O₄ [M + H]⁺: 545, found 545. 5-115

2-((S)-3-(3-((4-((R)-3- fluoropyrrolidine-1- carbonyl)-3- methylphenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B and I-39-3) LCMS (ESI) Calc'd for C₂₅H₂₈FN₆O₃ [M + H]⁺: 479, found 479. 5-116

2-((S)-3-(3-((4-((S)-3- methoxypyrrolidine-1- carbonyl)-3- methylphenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B and I-39-4.) LCMS (ESI) Calc'd for C₂₆H₃₁N₆O₄ [M + H]⁺: 491, found 491. 5-117

2-((S)-3-(3-((4-((R)-3- methoxypyrrolidine-1- carbonyl)-3- methylphenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H- pyran-3-yl)acetonitrile (from I-17B and I-39-5) LCMS (ESI) Calc'd for C₂₆H₃₁N₆O₄ [M + H]⁺: 491, found 491. 5-118

(S)-2-(3-(3-((3-methyl-4- (morpholine-4-carbonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-3-yl)acetonitrile (from I-17B) LCMS (ESI) Calc'd for C₂₅H₂₉N₆O₄ [M + H]⁺: 477, found 477. 5-119

2-((S)-3-(3-(((S or R)-1- hydroxy-2,2-dimethyl-1- (trifluoromethyl)-2,3- dihydro-1H-inden-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-3-yl)acetonitrile (from I-17B and I-36. Derived from Peak 1 on free pyridone via SFC: Chiralpak OJ-H, 20% MeOH in CO₂, Tr = 4.8 minutes) LCMS (ESI) Calc'd for C₂₅H₂₇F₃N₅O₃ [M + H]⁺: 502, found 502. 5-120

2-((S)-3-(3-((S or R)-1- hydroxy-2,2-dimethyl-1- (trifluoromethyl)-2,3- dihydro-1H-inden-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-3-yl)acetonitrile (from I-17B and I-36. Derived from Peak 2 on free pyridone via SFC: Chiralpak OJ-H, 20% MeOH in CO₂, Tr = 5.8 minutes) LRMS (ESI) Calc'd for C₂₅H₂₇F₃N₅O₃ [M + H]⁺: 502, found 502. 5-121

2-(1-(3-((2-(tert-butyl)- 1,1-dioxido-2,3- dihydrobenzo[d] isothiazol-5-yl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclopentyl)acetonitrile LRMS (ESI) Calc'd for C₂₄H₂₉N₆O₃S [M + H]⁺: 481, found 481. 5-122

2-(1-(3-((4-(tert- butylsulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl) cyclopentyl)acetonitrile LRMS (ESI) Calc'd for C₂₃H₂₈N₅O₃S [M + H]⁺: 454, found 454. 5-123

4-((1-(1-(cyanomethyl) cyclopentyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino-N,N- dimethylbenzene- sulfonamide LRMS (ESI) Calc'd for C₂₁H₂₅N₆O₃S [M + H]⁺: 441, found 441. 5-124

4-((1-(1-(cyanomethyl) cyclopentyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino) benzonitrile LRMS (ESI) Calc'd for C₂₀H₁₉N₆O [M + H]⁺: 359, found 359. 5-125

2-(1-(4-oxo-3-((1-oxo-1,3- dihydroisobenzofuran-5- yl)amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclopentyl)acetonitrile LRMS (ESI) Calc'd for C₂₁H₂₀N₅O₃ [M + H]⁺: 390, found 390. 5-126

(1-{3-[(3,3-dimethyl-1-oxo- 1,3-dihydro-2-benzofuran- 5-yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl} cyclopentyl)acetonitrile LRMS (ESI) Calc'd for C₂₃H₂₄N₅O₃ [M + H]⁺: 418, found 418. 5-127

tert-butyl 4-((1-(1- (cyanomethyl)cyclopentyl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyidin-3- yl)amino)benzoate LRMS (ESI) Calc'd for C₂₄H₂₈N₅O₃ [M + H]⁺: 434, found 434. 5-128

4-((1-(1-(cyanomethyl) cyclopentyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N- methylbenzamide. LRMS (ESI) Calc'd for C₂₁H₂₃N₆O₂ [M + H]⁺: 391, found 391. 5-129

2-(1-(3-((2-isopropyl-1- oxoisoindolin-5-yl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclopentyl)acetonitrile LRMS (ESI) Calc'd for C₂₄H₂₇N₆O₂ [M + H]⁺: 431, found 431. 5-130

4-((1-(1-(cyanomethyl) cyclopentyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)- N-isopropylbenzene- sulfonamide LRMS (ESI) Calc'd for C₂₂H₂₇N₆O₃S [M + H]⁺: 455, found 455. 5-131

4-((1-(1-(cyanomethyl) cyclopentyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N- methylbenzenesulfonamide LRMS (ESI) Calc'd for C₂₀H₂₃N₆O₃S [M + H]⁺: 427, found 427. 5-132

2-(1-(3-((4-(azetidin-1- ylsulfonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclopentyl)acetonitrile LRMS (ESI) Calc'd for C₂₂H₂₅N₆O₃S [M + H]⁺: 453, found 453. 5-133

2-(1-(3-((4-(ethylsulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)cyclopentyl) acetonitrile LRMS (ESI) Calc'd for C₂₁H₂₄N₅O₃S [M + H]⁺: 426, found 426. 5-134

N-(tert-butyl)-4-((1-(1- (cyanomethyl)cyclopentyl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N-methylbenzene sulfonamide LRMS (ESI) Calc'd for C₂₄H₃₁N₆O₃S [M + H]⁺: 483, found 483. 5-135

N-(tert-butyl)-4-((1-(1- (cyanomethyl)cyclopentyl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N-ethylbenzene sulfonamide LRMS (ESI) Calc'd for C₂₅H₃₃N₆O₃S [M + H]⁺: 497, found 497. 5-136

4-((1-(1-(cyanomethyl) cyclopentyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- diethylbenzenesulfonamide LRMS (ESI) Calc'd for C₂₃H₂₉N₆O₃S [M + H]⁺: 469, found 469. 5-137

tert-butyl 2-(4-((1-(1- (cyanomethyl)cyclopentyl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N-methylphenyl sulfonamido)-2- methylpropanoate LRMS (ESI) Calc'd for C₂₈H₃₇N₆O₅S [M + H]⁺: 569, found 569. 5-138

2-(1-(4-oxo-3-((1-oxo-2- (2,2,2-trifluoroethyl) isoindolin-5-yl)amino)- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclopentyl)acetonitrile LRMS (ESI) Calc'd for C₂₃H₂₂F₃N₆O₂ [M + H]⁺: 471, found 471. 5-139

ethyl 2-(4-((1-(1- (cyanomethyl)cyclopentyl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N- methylphenylsulfonamido)- 2-methylpropanoate LRMS (ESI) Calc'd for C₂₆H₃₃N₆O₅S [M + H]⁺: 541, found 541. 5-140

tert-butyl 2-(5-((1-(1- (cyanomethyl)cyclopentyl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-1-oxoisoindolin- 2-yl)-2-methylpropanoate LRMS (ESI) Calc'd for C₂₉H₃₅N₆O₄ [M + H]⁺: 531, found 531. 5-141

(R or S)-methyl 4- (cyanomethyl)-4-(4-oxo-3- ((4-(1,1,1-trifluoro-2- hydroxypropan-2-yl) phenyl)amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate (from I-32A) LRMS (ESI) Calc'd for C₂₄H₂₆F₃N₆O₄ [M + H]⁺: 519, found 519. 5-142

(R or S)-methyl 4- (cyanomethyl)-4-(4-oxo-3- ((4-(1,1,1-trifluoro-2- hydroxypropan-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate (from I-32B) LRMS (ESI) Calc'd for C₂₄H₂₆F₃N₆O₄ [M + H]⁺: 519, found 519. 5-143

(R or S)-methyl 4- (cyanomethyl)-4-(3-((1- hydroxy-1-(trifluoromethyl)- 2,3-dihydro-1H-inden-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidin- 1-carboxylate (from I-37A) LRMS (ESI) Calc'd for C₂₅H₂₆F₃N₆O₄ [M + H]⁺: 531, found 531. 5-144

(R or S)-methyl 4- (cyanomethyl)-4-(3-((1- hydroxy-1-(trifluoro- methyl)-2,3-dihydro- 1H-inden-5-yl)amino)- 4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl)piperidine-1- carboxylate (from I-37B) LRMS (ESI) Calc'd for C₂₅H₂₆F₃N₆O₄ [M + H]⁺: 531, found 531. 5-145

methyl 4-(cyanomethyl)-4- (3-((4-cyanophenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) Calc'd for C₂₂H₂₂N₇O₃ [M + H]⁺: 432, found 432. 5-146

methyl 4-(cyanomethyl)-4- (3-((4-fluorophenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) Calc'd for C₂₁H₂₂FN₆O₃ [M + H]⁺: 425, found 425. 5-147

methyl 4-(cyanomethyl)-4- (4-oxo-3-((4- (trifluoromethyl) phenyl)amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) Calc'd for C₂₂H₂₂F₃N₆O₃ [M + H]⁺: 475, found 475. 5-148

methyl 4-(cyanomethyl)-4- (4-oxo-3-(quinolin-6- ylamino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) Calc'd for C₂₄H₂₄N₇O₃ [M + H]⁺: 458, found 458. 5-149

methyl 4-(cyanomethyl)-4- (3-((4- (isopropylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) Calc'd for C₂₄H₂₉N₆O₅S [M + H]⁺: 513, found 513. 5-150

methyl 4-(3-((4-(tert- butylsulfonyl)phenyl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl)- 4-(cyanomethyl)piperidine- 1-carboxylate LRMS (ESI) Calc'd for C₂₅H₃₁N₆O₅S [M + H]⁺: 527, found 527. 5-151

2-((1R,2R)-2-fluoro-1-(3- ((3-methyl-4-(morpholine- 4-carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile (from I-19A) LRMS (ESI) Calc'd for C₂₆H₃₀FN₆O₃ [M + H]⁺: 493, found 493. 5-152

2-((1R,2R)-2-fluoro-1-(3- ((2-fluoropyridin-4-yl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)cyclohexyl)acetonitrile (from I-19A) LRMS (ESI) Calc'd for C₁₉H₁₉F₂N₆O [M + H]⁺: 385, found 385. 5-153

2-((1R,2R)-1-(3-((4-(4,4- difluoropiperidine-1- carbonyl)-3- methylphenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-2-fluorocyclohexyl) acetonitrile (from I-19A) LRMS (ESI) Calc'd for C₂₇H₃₀F₃N₆O₂ [M + H]⁺: 527, found 527. 5-154

2-((1R,2R)-2-fluoro-1-(3- ((3-methyl-4- (thiomorpholine-4- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile (from I-19A) LRMS (ESI) Calc'd for C₂₆H₃₀FN₆O₂S [M + H]⁺: 509, found 509. 5-155

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-(thiazolidine-3- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) Calc'd for C₂₉H₃₅N₆O₅S [M + H]⁺: 579, found 579. 5-156

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-2- methylthiazolidine-3- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak 1 via SFC on pyridone: Chiralpak AD-H, 20% iPrOH in CO₂, Tr = 17.8 minutes) LRMS (ESI) Calc'd for C₃₀H₃₇N₆O₅S [M + H]⁺: 593, found 593. 5-157

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-2- methylthiazolidine-3- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak 2 via SFC on pyridone: Chiralpak AD-H, 20% iPrOH in CO₂, Tr = 19.9 minutes) LRMS (ESI) Calc'd for C₃₀H₃₇N₆O₅S [M + H]⁺: 593, found 593. 5-158

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-2- methylthiomorpholine-4- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak 1 via SFC on pyridone: Chiralpak AD-H, 25% iPrOH in CO₂, Tr = 7.1 minutes) LRMS (ESI) Calc'd for C₃₁H₃₉N₆O₅S [M + H]⁺: 607, found 607. 5-159

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-2- methylthiomorpholine-4- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak 2 via SFC on pyridone: Chiralpak AD-H, 25% iPrOH in CO₂, Tr = 8.4 minutes) LRMS (ESI) Calc'd for C₃₁H₃₉N₆O₃S [M + H]⁺: 607, found 607. 5-160

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- ((S or R)-3-hydroxy-3- (trifluoromethyl)pyrrolidine- 1-carbonyl)-3-methylphenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A and I-39-2A) LRMS (ESI) Calc'd for C₃₁H₃₆F₃N₆O₆ [M + H]⁺: 645, found 645. 5-161

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- ((S or R)-3-hydroxy-3- (trifluoromethyl)pyrrolidine- 1-carbonyl)-3-methylphenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A and I-39-2B) LRMS (ESI) Calc'd for C₃₁H₃₆F₃N₆O₆ [M + H]⁺: 645, found 645. 5-162

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1,1,1-trifluoro- 2-hydroxy-4-isopropoxy-3,3- dimethyl-4-oxobutan-2-yl) phenyl)amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 2-carboxylate (from I-14-1A and I-35-2. Derived from Peak 1 via SFC on pyridone: Chiralpak IC, 30% MeOH in CO₂, Tr = 4.2 minutes) LRMS (ESI) Calc'd for C₃₃H₄₁F₃N₅O₇ [M + H]⁺: 676, found 676. 5-163

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1,1,1-trifluoro- 2-hydroxy-4-isopropoxy- 3,3-dimethyl-4-oxobutan-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A and I-35-2. Derived from Peak 2 via SFC on pyridone: Chiralpak IC, 30% MeOH in CO₂, Tr = 5.9 minutes) LRMS (ESI) Calc'd for C₃₃H₄₁F₃N₅O₇ [M + H]⁺: 676, found 676. 5-164

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3- (((S or R)-1-hydroxy- 2,2-dimethyl- 1-(trifluoromethyl)-2,3- dihydro-1H-inden-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A and I-36. Derived from Peak 1 via SFC on pyridone: Phenomenex Lux-4, 35% MeOH in CO₂, Tr = 3.1 minutes) LRMS (ESI) Calc'd for C₃₀H₃₅F₃N₅O₃ [M + H]⁺: 602, found 602. 5-165

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-(((S or R)-1-hydroxy-2,2-dimethyl- 1-(trifluoromethyl)-2,3- dihydro-1H-inden-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A and I-36. Derived from Peak 2 via SFC on pyridone: Phenomenex Lux-4, 35% MeOH in CO₂, Tr = 3.9 minutes) LRMS (ESI) Calc'd for C₃₀H₃₅F₃N₅O₅ [M + H]⁺: 602, found 602. 5-166

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1,1,1-trifluoro- 2-hydroxy-3,3- dimethylbutan-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A and I-37. Derived from Peak 1 via SFC on pyridone: Chiralpak AS-H, 15% MeOH in CO₂, Tr = 6.1 minutes) LRMS (ESI) Calc'd for C₃₀H₃₇F₃N₅O₅ [M + H]⁺: 604, found 604. 5-167

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1,1,1-trifluoro- 2-hydroxy-3,3- dimethylbutan-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-IA and I-37. Derived from Peak 2 via SFC on pyridone: Chiralpak AS-H, 15% MEOH in CO₂, Tr = 7.6 minutes) LRMS (ESI) Calc'd for C₃₀H₃₇F₃N₅O₅ [M + H]⁺: 604, found 604. 5-168

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-2,2,2- trifluoro-1-hydroxyethyl) phenyl)amino)-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A and I-25. Derived from Peak 1 via SFC on free pyridone: Chiralpak AD-H, 25% MeOH in CO₂, Tr = 3.8 minutes) LRMS (ESI) Calc'd for C₂₆H₂₉F₃N₅O₅ [M + H]⁺: 548, found 548. 5-169

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-2,2,2- trifluoro-1-hydroxyethyl) phenyl)amino)-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A and I-25. Derived from Peak 2 via SFC on free pyridone: Chiralpak AD-H, 25% MeOH in CO₂, Tr = 6.4 mins) LRMS (ESI) Calc'd for C₂₆H₂₉F₃N₅O₅ [M + H]⁺: 548, found 548. 5-170

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1,1,1-trifluoro- 2-hydroxypropan-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A and I-32A) LRMS (ESI) Calc'd for C₂₇H₃₁F₃N₅O₅ [M + H]⁺: 562, found 562. 5-171

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1,1,1-trifluoro- 2-hydroxypropan-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A and I-32B) LRMS (ESI) Calc'd for C₂₇H₃₁F₃N₅O₅ [M + H]⁺: 562, found 562. 5-172

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1,1,1-trifluoro- 2-methoxypropan-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A and I-33A) LRMS (ESI) Calc'd for C₂₈H₃₃F₃N₅O₅ [M + H]⁺: 576, found 576. 5-173

{(1R,2R)-1-[3-({4-[(1R or 1S)-1-(ethylamino)-2,2,2- trifluoroethyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl]-2- fluorocyclohexyl} acetonitrile (from I-19A. Derived from Peak A via SFC on pyridone: AS-H, 20% MEOH + 0.25% DMEA in CO₂, Tr = 4.4 minutes) LRMS (ESI) calc'd for C₂₄H₂₇F₄N₆O [M + H]⁺: 491, found 491. 5-174

{(1R,2R)-1-[3-({4-[(1R or 1S)-1-(ethylamino)-2,2,2- trifluoroethyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl]-2- fluorocyclohexyl} acetonitrile (from from I-19A. Derived from Peak B via SFC on pyridone, AS-H, 20% MeOH + 0.25% DMEA in CO₂, Tr = 5.9 minutes) LRMS (ESI) calc'd for C₂₄H₂₇F₄N₆O [M + H]⁺: 491, found 491. 5-175

[(1R,2R)-2-fluoro-1-{3-[(4- {1-methyl-1-[(1- methylethyl)amino]ethyl} phenyl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl} cyclohexyl]acetonitrile (from I-19A) LRMS (ESI) calc'd for C₂₆H₃₄FN₆O [M + H]⁺: 465, found 465. 5-176

{(1R,2R)-1-[3-({4-[(1R or 1S)-1-amino-2,2,2- trifluoroethyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl]-2- fluorocyclohexyl} acetonitrile (from I-19A and I-29A) LRMS (ESI) calc'd for C₂₂H₂₃F₄N₆O [M + H]⁺: 463, found 463. 5-177

{(1R,2R)-1-[3-({4-[(1S or 1R)-1-amino-2,2,2- trifluoroethyl] phenyl}amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]-2- fluorocyclohexyl} acetonitrile (from I-19A and I-29B) LRMS (ESI) calc'd for C₂₂H₂₃F₄N₆O [M + H]⁺: 463, found 463. 5-178

[(3S)-3-{3-[(2-tert-butyl- 1,1-dioxido-2,3-dihydro- 1,2-benzisothiazol-5-yl) amino]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl}tetrahydro- 2H-pyran-3-yl] acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₄H₂₉N₆O₄S [M + H]⁺: 497, found 497. 5-179

{(3S)-3-[3-({4-[(1- methylethyl)sulfonyl] phenyl}amino)-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]tetrahydro-2H-pyran-3- yl}acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₂H₂₆N₅O₄S [M + H]⁺: 456, found 456. 5-180

4-({1-[(3R,4S or 3S,4R)-3- (cyanomethyl)-4- fluorotetrahydro-2H-pyran- 3-yl]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-3-yl}amino)- N,N-dimethylbenzene- sulfonamide (from I-7-3A) LRMS (ESI) calc'd for C₂₁H₂₄FN₆O₄S [M + H]⁺: 475, found 475. 5-181

4-({1-[(3S,4R or 3S,4R)-3- (cyanomethyl)-4- fluorotetrahydro-2H-pyran- 3-yl]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-3-yl}amino)-N,N- dimethylbenzene- sulfonamide (from I-7-3B) LRMS (ESI) calc'd for C₂₁H₂₄FN₆O₄S [M + H]⁺: 475, found 475. 5-182

N-tert-butyl-4-({1-[(3S)-3- (cyanomethyl)tetrahydro- 2H-pyran-3-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl}amino)-N- methylbenzenesulfonamide (from I-17B) LRMS (ESI) calc'd for C₂₄H₃₁N₆O₄S [M + H]⁺: 499, found 499. 5-183

[(3S)-3-(3-{[4-(tert- butylsulfonyl)phenyl] amino}-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₃H₂₈N₅O₄S [M + H]⁺: 470, found 470. 5-184

N-tert-butyl-4-({1-[(3S)-3- (cyanomethyl)tetrahydro- 2H-pyran-3-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl}amino) benzenesulfonamide (from I-17B) LRMS (ESI) calc'd for C₂₃H₂₉N₆O₄S [M + H]⁺: 485, found 485. 5-185

tert-butyl [5-({1-[(3S)-3- (cyanomethyl)tetrahydro- 2H-pyran-3-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl}amino)-1,1- dioxido-1,2-benzisothiazol- 2(3H)-yl]acetate (from I-17B) LRMS (ESI) calc'd for C₂₆H₃₁N₆O₆S [M + H]⁺: 555, found 555. 5-186

tert-butyl 3-{[4-({1-[(3S)-3- (cyanomethyl)tetrahydro- 2H-pyran-3-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3- yl}amino)phenyl]sulfonyl}- 3-methylbutanoate (from I- 17B) LRMS (ESI) calc'd for C₂₄H₂₆N₅O₆S [M − C₄H₁₀ + H]⁺: 514, found 514. 5-187

{(3S)-3-[3-({4-[(1R or 1S)-1-amino-2,2,2- trifluoroethyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl}acetonitrile (from I-17B and I-29A) LRMS (ESI) calc'd for C₂₁H₂₂F₃N₆O₂ [M + H]⁺: 447, found 447. 5-188

{(3S)-3-[3-({4-[(1S or 1R)- 1-amino-2,2,2- trifluoroethyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl}acetonitrile (from I-17B and I-29B) LRMS (ESI) calc'd for C₂₁H₂₂F₃N₆O₂ [M + H]⁺: 447, found 447. 5-189

{(3S)-3-[3-({4-[(1R or 1S)- 1-(tert-butylamino)-2,2,2- trifluoroethyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1- yl]tetrahydro-2H-pyran-3- yl}acetonitrile (from I-17B. Derived from Peak A via SFC: IA column, 35% MeOH in CO₂, Tr = 2.8 minutes on OBn intermediate) LRMS (ESI) calc'd for C₂₅H₂₉F₃N₆O₂Na [M + Na]⁺: 525, found 525. 5-190

{(3S)-3-[3-({4-[(1S or 1R)- 1-(tert-butylamino)-2,2,2- trifluoroethyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl] tetrahydro-2H-pyran-3- yl}acetonitrile (from I-17B. Derived from Peak B via SFC: IA column, 35% MeOH in CO₂, Tr = 3.9 minutes on OBn intermediate) LRMS (ESI) calc'd for C₂₅H₃₀F₃N₆O₂ [M + H]⁺: 503, found 503. 5-191

[(3S)-3-(3-{[4- (cyclopentylsulfonyl) phenyl]amino}-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₄H₂₈N₅O₄S [M + H]⁺: 482, found 482. 5-192

{(3S)-3-[4-oxo-3-({4- [(1,1,2-trimethylpropyl) sulfonyl]phenyl}amino)- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]tetrahydro-2H-pyran-3- yl}acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₅H₃₂N₅O₄S [M + H]⁺: 498, found 498. 5-193

[(3S)-3-(3-{[4- (cyclohexylsulfonyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 3-yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₅H₃₀N₅O₄S [M + H]⁺: 496, found 496. 5-194

(2S,5S)-tert-butyl 5-(3-((4- ((R or S)-1-(tert- butylamino)-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl)- 5-(cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A. Derived from Peak A via SFC: AD-H, 15% 2-propanol + 0.25% DMEA in CO₂, Tr = 4.9 minutes on OBn intermediate) LRMS (ESI) calc'd for C₃₀H₃₇F₃N₆O₄Na [M + Na]⁺: 625, found 625. 5-195

(2S,5S)-tert-butyl 5-(3-((4- ((R or S)-1-(tert- butylamino)-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl)- 5-(cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A. Derived from Peak B via SFC: AD-H, 15% 2-propanol + 0.25% DMEA in CO₂, Tr = 5.5 minutes on OBn intermediate) LRMS (ESI) calc'd for C₃₀H₃₈F₃N₆O₄ [M + H]⁺: 603, found 603. 5-196

{(3S)-3-[3-({4-[(1,1- dimethylpropyl)sulfonyl] phenyl}amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl}acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₄H₃₀N₅O₄S [M + H]⁺: 484, found 484. 5-197

[(3S)-3-{3-[(2-cyclopentyl- 1-oxo-2,3-dihydro-1H- isoindol-5-yl)amino]-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydro-2H-pyran-3- yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₆H₂₉N₆O₃ [M + H]⁺: 473, found 473. 5-198

{(3S)-3-[4-oxo-3-({4- [(1R or 1S)-2,2,2- trifluoro-1-pyrrolidin- 1-ylethyl]phenyl}amino)- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl] tetrahydro-2H-pyran-3- yl}acetonitrile (from I-17B. Derived from Peak A via SFC: IB, 20% MeOH + 0.25% DMEA in CO₂, Tr = 7.4 minutes on OBn intermediate) LRMS (ESI) calc'd for C₂₅H₂₈F₃N₆O₂ [M + H]⁺: 501, found 501. 5-199

{(3S)-3-[4-oxo-3-({4- [(1S or 1R)-2,2,2- trifluoro-1- pyrrolidin-1-ylethyl] phenyl}amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl]tetrahydro-2H-pyran-3- yl}acetonitrile (from I-17B. Derived from Peak B via SFC: IB, 20% MeOH + 0.25% DMEA in CO₂, Tr = 7.9 minutes on OBn intermediate) LRMS (ESI) calc'd for C₂₅H₂₈F₃N₆O₂ [M + H]⁺: 501, found 501. 5-200

{(3S)-3-[4-oxo-3-({4- [(1S or 1R)-1-pyrrolidin-1- ylethyl]phenyl}amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl}acetonitrile (from I-17B. Derived from Peak A via SFC: AS-H, 15% MeOH + 0.25% DMEA in CO₂, Tr = 10.3 minutes on OBn intermediate) LRMS (ESI) calc'd for C₂₅H₃₁N₆O₂ [M + H]⁺: 447, found 447. 5-201

{(3S)-3-[4-oxo-3-({4- [(1R or 1S)-1-pyrrolidin-1- ylethyl]phenyl}amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl}acetonitrile (from I-17B. Derived from Peak B via SFC, AS-H, 15% MeOH + 0.25% DMEA in CO₂, Tr = 12.0 minutes on OBn intermediate) LRMS (ESI) calc'd for C₂₅H₃₁N₆O₂ [M + H]⁺: 447, found 447. 5-202

{(3S)-3-[3-({4-[(2,2- dimethylcyclopentyl) sulfonyl]phenyl} amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl]tetrahydro- 2H-pyran-3-yl}acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₆H₃₂N₅O₄S [M + H]⁺: 510, found 510. 5-203

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (morpholinosulfonyl) phenyl)amino)-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₃₅N₆O₇S [M + H]⁺: 599, found 599. 5-204

[(3S)-3-(3-{[4-(morpholin- 4-ylsulfonyl)phenyl] amino}-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₃H₂₇N₆O₅S [M + H]⁺: 499, found 499. 5-205

[(3S)-3-{4-oxo-3-[(4- {(1R or 1S)-2,2,2- trifluoro-1-[(1- methylethyl)amino]ethyl} phenyl)amino]-4,5-dihydro- 1H-pyrazolo[4,3-c] pyridin-1-yl}tetrahydro- 2H-pyran-3-yl]acetonitrile (from I-17B. Derived from Peak A via SFC: OJ-H, 15% MeOH + 0.25% DMEA in CO₂, Tr = 4.1 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₄H₂₈F₃N₆O₂ [M + H]⁺: 489, found 489. 5-206

[(3S)-3-{4-oxo-3-[(4- {(1S or 1R)-2,2,2- trifluoro-1-[(1- methylethyl)amino]ethyl} phenyl)amino]-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl} tetrahydro-2H-pyran-3- yl]acetonitrile (from I-17B. Derived from Peak B via SFC: OJ-H, 15% MeOH + 0.25% DMEA in CO₂, Tr = 4.9 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₄H₂₈F₃N₆O₂ [M + H]⁺: 489, found 489. 5-207

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- ((R or S)-1-(ethylamino)- 2,2,2-trifluoroethyl) phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak A via SFC: AS-H, 15% MeOH + 0.25% DMEA in CO₂, Tr = 3.8 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₈H₃₄F₃N₆O₄ [M + H]⁺: 575, found 575. 5-208

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4-((R or S)-1-(ethylamino)-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak B via SFC: AS-H, 15% MeOH + 0.25% DMEA in CO₂, Tr = 5.8 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₈H₃₄F₃N₆O₄ [M + H]⁺: 575, found 575. 5-209

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((R or S)-2,2,2-trifluoro- 1-(isopropylamino) ethyl)phenyl)amino)-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak A via SFC: AD-H, 20% 2-propanol + 0.25% DMEA in CO₂, Tr = 3.9 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₉H₃₆F₃N₆O₄ [M + H]⁺: 589, found 589. 5-210

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((R or S)-2,2,2- trifluoro-1- (isopropylamino)ethyl) phenyl)amino)-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak B via SFC, AD-H, 20% 2-propanol + 0.25% DMEA in CO₂, Tr = 5.1 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₉H₃₆F₃N₆O₄ [M + H]⁺: 589, found 589. 5-211

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1-(pyrrolidin- 1-yl)ethyl)phenyl)amino)- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak A via SFC: Lux-2, 40% MeOH + 0.25% DMEA in CO₂, Tr = 10.4 minutes on pyridone final compound) LRMS (ESI) calc'd for C₃₀H₃₉N₆O₄ [M + H]⁺: 547, found 547. 5-212

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-1-(pyrrolidin- 1-yl)ethyl)phenyl)amino)- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H-pyran- 2-carboxylate (from I-14-1A. Derived from Peak B via SFC: Lux-2, 40% MeOH + 0.25% DMEA in CO₂, Tr = 11.8 mins on pyridone final compound) LRMS (ESI) calc'd for C₃₀H₃₉N₆O₄ [M + H]⁺: 547, found 547. 5-213

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- ((R or S)-1-(dimethylamino)- 2,2,2-trifluoroethyl) phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak A via SFC: ID, 25% 2-propanol + 0.25% DMEA in CO₂, Tr = 5.3 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₈H₃₄F₃N₆O₄ [M + H]⁺: 575, found 575. 5-214

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- ((R or S)-1-(dimethylamino)- 2,2,2-trifluoroethyl) phenyl)amino)-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. Derived from Peak B via SFC: ID, 25% 2- propanol + 0.25% DMEA in CO₂, Tr = 6.9 minutes on pyridone final compound) LRMS (ESI) calc'd for C₂₈H₃₄F₃N₆O₄ [M + H]⁺: 575, found 575. 5-215

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- (quinolin-6-ylamino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₂₉N₆O₄ [M + H]⁺: 501, found 501. 5-216

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- cyanoquinolin-6-yl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₂₈N₇O₄ [M + H]⁺: 526, found 526. 5-217

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- methylquinolin-6-yl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₃₁N₆O₄ [M + H]⁺: 515, found 515. 5-218

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (3,5-dimethyl-1H- pyrazol-1-yl)phenyl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₉H₃₄N₇O₄ [M + H]⁺: 544, found 544. 5-219

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-(1H-pyrazol-1- yl)phenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H- pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₃₂N₇O₄ [M + H]⁺: 530, found 530. 5-220

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (2,2-dimethylmorpholine- 4-carbonyl)-3- methylphenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₂H₄₁N₆O₆ [M + H]⁺: 605, found 605. 5-221

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- (quinolin-3-ylamino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₂₉N₆O₄ [M + H]⁺: 501, found 501. 5-222

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- (dimethylamino)quinolin-6- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₉H₃₄N₇O₄ [M + H]⁺: 544, found 544. 5-223

(2S,5S)-tert-butyl 5-(3-((2- carbamoylquinolin-6- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₀N₇O₅ [M + H]⁺: 544, found 544. 5-224

(S)-2-(3-(4-oxo-3-((4-(1- (trifluoromethyl) cyclopropyl)phenyl) amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 3-yl)acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₃H₂₃F₃N₅O₂ [M + H]⁺: 458, found 458. 5-225

(S)-2-(3-(3-((2- (dimethylamino)quinolin- 6-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-3-yl)acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₄H₂₆N₇O₂ [M + H]⁺: 444, found 444. 5-226

(S)-2-(3-(3-((2- methylquinolin-6-yl) amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1-yl) tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₃H₂₃N₆O₂ [M + H]⁺: 415, found 415. 5-227

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- morpholinoquinolin-6- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₁H₃₆N₇O₅ [M + H]⁺: 586, found 586. 5-228

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- ((S)-2- methylmorpholino)quinolin- 6-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₂H₃₈N₇O₅ [M + H]⁺: 600, found 600. 5-229

(2S,5S)-tert-butyl 5-(3-((2- (8-oxa-3- azabicyclo[3.2.1]octan-3- yl)quinolin-6-yl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-5-(cyanomethyl) tetrahydro-2H-pyran- 2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₅N₆O₅S [M + H]⁺: 612, found 612. 5-230

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-(propan-2-yl-(S or R)- sulfonimidoyl)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) (derived from Peak 2, SFC on OBn intermediate using Chiralcel OJ-H, 45% MeOH in CO₂, Tr = 7.6 minutes) LRMS (ESI) calc'd for C₂₇H₃₅N₆O₅S [M + H]⁺: 555, found 555. 5-231

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-(propan-2-yl-(S or R)- sulfonimidoyl)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) (derived from Peak 1, SFC on OBn intermediate using Chiralcel OJ-H, 45% MeOH in CO₂, Tr = 4.1 minutes) LRMS (ESI) calc'd for C₂₇H₃₅N₆O₅S [M + H]⁺: 555, found 555. 5-232

2-((3S)-3-(4-oxo-3-((4- (propan-2-yl-(S or R)- sulfonimidoyl)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B) (derived from Peak 2, SFC on OBn intermediate using Chiralcel OJ-H, 20% MeOH in CO₂, Tr = 10.3 minutes) LRMS (ESI) calc'd for C₂₂H₂₇N₆O₃S [M + H]⁺: 455, found 455. 5-233

2-((3S)-3-(4-oxo-3-((4- (propan-2-yl-(S or R)- sulfonimidoyl)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-3- yl)acetonitrile (from I-17B) (derived from Peak 1, SFC on OBn intermediate using Chiralcel OJ-H, 20% MeOH in CO₂, Tr = 8.7 minutes) LRMS (ESI) calc'd for C₂₂H₂₇N₆O₃S [M + H]⁺: 455, found 455. 5-234

4-({1-[(1R,2R)-1- (cyanomethyl)-2- fluorocyclohexyl]-4-oxo- 4,5-dihydro-1H-pyrazolo [4,3-c]pyridin-3-yl} amino)-N,N-dimethyl- benzenesulfonamide (from I-19A) LRMS (ESI) calc'd for C₂₂H₂₆N₆O₃SF [M + H]⁺: 473, found 473. 5-235

(2S,5S)-tert-butyl 5-(3- ((4-(tert- butylsulfonyl)phenyl) amino)-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl)-5-(cyanomethyl) tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₃₆N₅O₆S [M + H]⁺: 570, found 570. 5-236

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (cyclopropylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₂N₅O₆S [M + H]⁺: 554, found 554. 5-237

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (isopropylsulfonyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₇H₃₄N₅O₆S [M + H]⁺: 556, found 556. 5-238

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- (dimethylcarbamoyl) quinolin-6-yl)amino)- 4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₀H₃₄N₇O₅ [M + H]⁺: 572, found 572. 5-239

4-({1-[(3R or 3S)-3- (cyanomethyl)tetrahydrofuran- 3-yl]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-3- yl}amino)benzonitrile (Chiral HPLC on free pyridone using Chiralpak IA, 0.1% TEA, 1:1 Hex:EtOH, Tr = 3.1 minutes) LRMS (ESI) calc'd for C₁₉H₁₇N₅O₂Cl [M + H]⁺: 361, found 361. 5-240

4-({1-[(3S or 3R)-3- (cyanomethyl)tetrahydrofuran- 3-yl]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-3- yl}amino)benzonitrile (Chiral HPLC on free pyridone using Chiralpak IA, 0.1% TEA, 1:1 Hex:EtOH, Tr = 7.5 minutes) LRMS (ESI) calc'd for C₁₉H₁₇N₅O₂Cl [M + H]⁺: 361, found 361. 5-241

[(3R or 3S)-3-{3-[(4- chlorophenyl)amino]-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydrofuran-3- yl]acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, 30:70 DCM/MeOH, Tr = 3.3 minutes) LRMS (ESI) calc'd for C₁₈H₁₇ClN₅O₂ [M + H]⁺: 370, found 370. 5-242

[(3S or 3R)-3-{3-[(4- chlorophenyl)amino]-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydrofuran-3- yl]acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, 30:70 DCM/MeOH, Tr = 7.1 minutes) LRMS (ESI) calc'd for C₁₈H₁₇ClN₅O₂ [M + H]⁺: 370, found 370. 5-243

[(3R or 3S)-3-{3-[(4-chloro- 8-fluoroquinolin-6- yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1- yl}tetrahydrofuran-3- yl]acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, Hex (0.1% TEA):IPA = 75:25, Tr = 5.2 minutes) LRMS (ESI) calc'd for C₂₁H₁₇ClFN₆O₂ [M + H]⁺: 439, found 439. 5-244

[(3S or 3R)-3-{3-[(4-chloro- 8-fluoroquinolin-6- yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1- yl}tetrahydrofuran-3- yl]acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, Hex (0.1% TEA):IPA = 75:25, Tr = 6.6 minutes) LRMS (ESI) calc'd for C₂₁H₁₇ClFN₆O₂ [M + H]⁺: 439, found 439. 5-245

[(3R or 3S)-3-{3-[(4- fluoroquinolin-6-yl)amino]- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydrofuran-3- yl]acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, Hex (0.1% TEA):EtOH = 50:50, Tr = 3.2 minutes) LRMS (ESI) calc'd for C₂₁H₁₈FN₆O₂ [M + H]⁺: 405, found 405. 5-246

[(3S or 3R)-3-{3-[(4- fluoroquinolin-6-yl)amino]- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydrofuran-3- yl]acetonitrile (Chiral HPLC on free pyridone Chiralpak IA, Hex (0.1% TEA):EtOH = 50:50, Tr = 5.0 minutes) LRMS (ESI) calc'd for C₂₁H₁₈FN₆O₂ [M + H]⁺: 405, found 405. 5-247

(S or R)-2-(3-(3-((2-(tert- butyl)-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1- yl)tetrahydrofuran-3- yl)acetonitrile (Chiral HPLC on free pyridone Chiralpak IA, MeOH (0.1% TEA) Tr = 15.5 minutes) LRMS (ESI) calc'd for C₂₃H₂₇N₆O₄S [M + H]⁺: 483, found 483. 5-248

(R or S)-2-(3-(3-((2-(tert- butyl)-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1- yl)tetrahydrofuran-3- yl)acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, MeOH (0.1% TEA), Tr = 23.5 minutes) LRMS (ESI) calc'd for C₂₃H₂₇N₆O₄S [M + H]⁺: 483, found 483. 5-249

(S or R)-2-(3-(3-((4-(tert- butylsulfonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydrofuran-3- yl)acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, 1:1 hexanes (0.1% DEA): iPrOH (0.1% DEA), Tr = 15.3 minutes) LRMS (ESI) calc'd for C₂₂H₂₆N₅O₄S [M + H]⁺: 456, found 456. 5-250

(R or S)-2-(3-(3-((4-(tert- butylsulfonyl)phenyl) amino)-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydrofuran-3- yl)acetonitrile (Chiral HPLC on free pyridone using Chiralpak IA, 1:1 hexanes (0.1% DEA): iPrOH (0.1% DEA), Tr = 37.6 minutes) LRMS (ESI) calc'd for C₂₃H₂₇N₆O₄S [M + H]⁺: 456, found 456. 5-251

2-(4-(3-((2-(tert-butyl)- 1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-4-yl)acetonitrile LRMS (ESI) calc'd for C₂₄H₂₉N₆O₄S [M + H]⁺: 497, found 497. 5-252

2-(4-(3-((4-(tert- butylsulfonyl)phenyl) amino)-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-4- yl)acetonitrile LRMS (ESI) calc'd for C₂₃H₂₈N₅O₄S [M + H]⁺: 470, found 470. 5-253

N-(tert-butyl)-4-((1-(4- (cyanomethyl)tetrahydro- 2H-pyran-4-yl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N- methylbenzenesulfonamide LRMS (ESI) calc'd for C₂₄H₃₁N₆O₄S [M + H]⁺: 499, found 499. 5-254

4-((1-(4- (cyanomethyl)tetrahydro- 2H-pyran-4-yl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₁H₂₅N₆O₄S [M + H]⁺: 457, found 457. 5-255

2-((3S,4S or 3R,4R)-4-(3-((2- (tert-butyl)-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-3- fluorotetrahydro-2H-pyran- 4-yl)acetonitrile (from racemic cis I-22) (Chiral HPLC on free pyridone using AD-H; Hexanes (0.1% DEA):EtOH (0.1% DEA) = 50:50, Tr = 21 minutes) LRMS (ESI) calc'd for C₂₄H₂₈FN₆O₄S [M + H]⁺: 515 found 515. 5-256

2-((3R,4R or 3S,4S)-4-(3-((2- (tert-butyl)-1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-3- fluorotetrahydro-2H-pyran- 4-yl)acetonitrile (from racemic cis I-22) (Chiral HPLC on freee pyridone using AD-H; Hexanes (0.1% DEA):EtOH (0.1% DEA) = 50:50, Tr = 26 minutes) LRMS (ESI) calc'd for C₂₄H₂₈FN₆O₄S [M + H]⁺: 515 found 515. 5-257

2-((3S,4S or 3R,4R)-3-fluoro- 4-(3-(3-methyl-4- (morpholine-4- carbonyl)phenylamino)-4- oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)-tetrahydro- 2H-pyran-4-yl)acetonitrile (derived from I-22B) LRMS (ESI) calc'd for C₂₅H₂₈FN₆O₄ [M + H]⁺: 495, found 495. 5-258

2-((3R,4R or 3S,4S)-3- fluoro-4-(3-((3-methyl-4- (morpholine-4- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-4- yl)acetonitrile (derived from I-22A) LRMS (ESI) calc'd for C₂₅H₂₈FN₆O₄ [M + H]⁺: 495, found 495. 5-259

2-((3R,4R or 3S,4S)-4-(3-((2- (tert-butyl)-1-oxoisoindolin- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-3- fluorotetrahydro-2H-pyran- 4-yl)acetonitrile (derived from I-22A) LRMS (ESI) calc'd for C₂₅H₂₈FN₆O₃ [M + H]⁺: 479, found 479. 5-260

2-((3S,4S or 3R,4R)-4-(3-(2- tert-butyl-1-oxoisoindolin-5- ylamino)-4-oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)-3-fluoro- tetrahydro-2H-pyran-4- yl)acetonitrile (derived from I-22B) LRMS (ESI) calc'd for C₂₅H₂₈FN₆O₃ [M + H]⁺: 479, found 479. 5-261

2-((3S,4S or 3R,4R)-3-fluoro- 4-(3-(3-methyl-4- (thiomorpholine-4- carbonyl)phenylamino)-4- oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)-tetrahydro- 2H-pyran-4-yl)acetonitrile (derived from I-22B) LRMS (ESI) calc'd for C₂₅H₂₈FN₆O₃S [M + H]⁺: 511, found 511. 5-262

2-((3R,4R or 3S,4S)-3-fluoro- 4-(3-((3-methyl-4- (thiomorpholine-4- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-4- yl)acetonitrile (derived from I-22A) LCMS (ESI) calc'd for C₂₅H₂₈FN₆O₃S [M + H]⁺: 511, found 511. 5-263

2-((3S,4S or 3R,4R)-3-fluoro- 4-(4-oxo-3-((4-((S or R)-2- (trifluoromethyl)piperidin-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-4-yl)acetonitrile (derived from I-22B and I- 54B) LRMS (ESI) calc'd for C₂₅H₂₇F₄N₆O₂ [M + H]⁺: 519, found 519. 5-264

2-((3S,4S or 3R,4R)-3-fluoro- 4-(4-oxo-3-((4-((R or S)-2- (trifluoromethyl)piperidin-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-4-yl)acetonitrile (derived from I-22B and I- 54A) LRMS (ESI) calc'd for C₂₅H₂₇F₄N₆O₂ [M + H]⁺: 519, found 519. 5-265

2-((3R,4R or 3S,4S)-3-fluoro- 4-(4-oxo-3-((4-((S or R)-2- (trifluoromethyl)piperidin-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-4-yl)acetonitrile (derived from I-22A and I- 54B) LRMS (ESI) calc'd for C₂₅H₂₇F₄N₆O₂ [M + H]⁺: 519, found 519. 5-266

2-((3R,4R or 3S,4S)-3-fluoro- 4-(4-oxo-3-((4-((R or S)-2- (trifluoromethyl)piperidin-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-4-yl)acetonitrile (derived from I-22A and I- 54A) LRMS (ESI) calc'd for C₂₅H₂₇F₄N₆O₂ [M + H]⁺: 519, found 519. 5-267

2-((3S,4S or 3R,4R)-4-(3-((4- ((R or S)-1-(tert- butylamino)-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)-3-fluorotetrahydro- 2H-pyran-4-yl)acetonitrile (from I-22B. The mixture was purified by Chiral HPLC with a Venusil Chiral ODH column, with hexanes:EtOH = 80:20, Tr = 27.5 minutes) LRMS (ESI) calc'd for C₂₅H₂₉F₄N₆O₂ [M + H]⁺: 521 found 521. 5-268

2-((3S,4S or 3R,4R)-4-(3-((4- ((S or R)-1-(tert- butylamino)-2,2,2- trifluoroethyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1-yl)- 3-fluorotetrahydro-2H- pyran-4-yl)acetonitrile (from I-22B. The mixture was purified by Chiral HPLC with a Venusil Chiral ODH column, with hexanes:EtOH = 80:20, Tr = 35.0 minutes) LRMS (ESI) calc'd for C₂₅H₂₉F₄N₆O₂ [M + H]⁺: 521 found 521. 5-269

2-((3R,4R or 3S,4S)-4-(3-((4- ((R or S)-1-(tert- butylamino)-2,2,2- trifluoroethyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)-3-fluorotetrahydro-2H- pyran-4-yl)acetonitrile (from I-22A. The mixture was purified by Chiral HPLC with a Venusil Chiral ODH column using hexanes:EtOH (80:20), Tr = 38.0 minutes) LRMS (ESI) calc'd for C₂₅H₂₉F₄N₆O₂ [M + H]⁺: 521 found 521. 5-270

2-((3R,4R or 3S,4S)-4-(3- ((4-((S or R)-1-(tert- butylamino)-2,2,2- trifluoroethyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1-yl)- 3-fluorotetrahydro-2H- pyran-4-yl)acetonitrile (from I-22A. The mixture was purified by Chiral HPLC with a Venusil Chiral ODH column using hexanes:EtOH (80:20), Tr = 45.0 minutes) LRMS (ESI) calc'd for C₂₅H₂₉F₄N₆O₂ [M + H]⁺: 521 found 521. 5-271

2-[(3S,4S or 3R,4R)-4-(3- {[1,1-dioxo-2-(piperidin-4- yl)-3H-1,2-benzothiazol-5- yl]amino}-4-oxo-5H- pyrazolo[4,3-c]pyridin-1-yl)- 3-fluorooxan-4- yl]acetonitrile (from I-22B) LRMS (ESI) calc'd for C₂₅H₂₉FN₇O₄S [M + H]⁺: 542, found 542. 5-272

2-((3R,4R or 3S,4S)-4-(3- ((1,1-dioxido-2-(piperidin-4- yl)-2,3-dihydrobenzo [d]isothiazol-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-3- fluorotetrahydro-2H-pyran- 4-yl)acetonitrile (from I- 22A) LRMS (ESI) calc'd for C₂₅H₂₉FN₇O₄S [M + H]⁺: 542, found 542. 5-273

tert-butyl (3R,4R)-4- (cyanomethyl)-3-fluoro-4- {3-[(4-{1-methyl-1-[(1- methylethyl)amino]ethyl} phenyl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl}piperidine-1- carboxylate (from I-7-2B) LRMS (ESI) calc'd for C₃₀H₄₁FN₇O₃ [M + H]⁺: Calc'd 566, found 566. 5-274

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4-(2- (isopropylamino)propan-2- yl)phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₀H₄₁N₆O₄ [M + H]⁺: Calc'd 549, found 549. 5-275

tert-butyl (3R,4R)-4- (cyanomethyl)-3-fluoro-4-(3- {[4-(1-methoxyethyl)phenyl] amino}-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate (from I-7-2B, as a mixture of ether diastereomers) LRMS (ESI) calc'd for C₂₇H₃₁F₄N₆O₄ [M + H]⁺: Calc'd 579, found 579. 5-276

tert-butyl 4-(cyanomethyl)- 4-{3-[(4-{1-methyl-1-[(1- methylethyl)amino]ethyl} phenyl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl}piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₀H₄₂N₇O₃ [M + H]⁺: Calc'd 548, found 548. 5-277

2-((3R,4R or 3S,4S)-4-(3- ((1,1-dioxido-2-(1-(2,2,2- trifluoroethyl)piperidin-4- yl)-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-3- fluorotetrahydro-2H-pyran- 4-yl)acetonitrile (from I- 22A) LRMS (ESI) calc'd for C₂₇H₃₀F₄N₇O₄S [M + H]⁺: 624, found 624. 5-278

2-((3S,4S or 3R,4R)-4-(3- ((1,1-dioxido-2-(1-(2,2,2- trifluoroethyl)piperidin-4- yl)-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-3- fluorotetrahydro-2H-pyran- 4-yl)acetonitrile (from I- 22B) LRMS (ESI) calc'd for C₂₇H₃₀F₄N₇O₄S [M + H]⁺: 624, found 624. 5-279

(3R,4R)-tert-butyl 4- (cyanomethyl)-3-fluoro-4-(3- ((3-methyl-4- (thiomorpholine-4- carbonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate (from I-7-2B) LRMS (ESI) Calc'd for C₃₀H₃₇FN₇O₄S [M + H]⁺: 610, found 610. 5-280

(S or R) tert-butyl 4-(3-((4- (1-benzyl-3-(trifluoromethyl) pyrrolidin-3- yl)phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate (Derived from free pyridone Peak 2 via SFC: AD-H, 30% MeOH + 0.25% DMEA in CO₂, Tr = 7.8 minutes) LRMS (ESI) Calc'd for C₃₆H₄₁F₃N₇O₃ [M + H]⁺: 676, found 676. 5-281

(S or R) tert-butyl 4-(3-((4- (1-benzyl-3-(trifluoromethyl) pyrrolidin-3- yl)phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (cyanomethyl)piperidine-1- carboxylate (Derived from free pyridone Peak 1 via SFC: AD-H, 30% MeOH + 0.25% DMEA in CO₂, Tr = 4.7 minutes) LRMS (ESI) Calc'd for C₃₆H₄₁F₃N₇O₃ [M + H]⁺: 676, found 676. 5-282

(S or R) tert-butyl 4- (cyanomethyl)-4-(4-oxo-3- ((4-(3- (trifluoromethyl)pyrrolidin- 3-yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine-1- carboxylate (Derived from free pyridone Peak 1 via SFC: ID, 35% MeOH + 0.25% DMEA in CO₂, Tr = 3.5 minutes) LRMS (ESI) Calc'd for C₂₉H₃₅F₃N₇O₃ [M + H]⁺: 586, found 586. 5-283

(S or R) tert-butyl 4- (cyanomethyl)-4-(4-oxo-3- ((4-(3- (trifluoromethyl)pyrrolidin- 3-yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate (Derived from free pyridone Peak 2 via SFC: ID, 35% MeOH + 0.25% DMEA in CO₂, Tr = 5.2 minutes) LRMS (ESI) Calc'd for C₂₉H₃₅F₃N₇O₃ [M + H]⁺: 586, found 586. 5-284

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((R or S)-3- (trifluoromethyl)pyrrolidin- 3-yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A. Derived from free pyridone Peak 1 via SFC: ID, 35% MeOH + 0.25% DMEA in CO₂, Tr = 3.9 minutes) LRMS (ESI) Calc'd for C₂₉H₃₄F₃N₆O₄ [M + H]⁺: 587, found 587. 5-285

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((R or S)-3- (trifluoromethyl)pyrrolidin- 3-yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A. Derived from free pyridone Peak 2 via SFC: ID, 35% MeOH + 0.25% DMEA in CO₂, Tr = 5.7 minutes) LRMS (ESI) Calc'd for C₂₉H₃₄F₃N₆O₄ [M + H]⁺: 587, found 587. 5-286

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-2- (trifluoromethyl)piperidin-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A. Derived from free pyridone Peak 1 via SFC: ID, 30% iPrOH + 0.25% DMEA in CO₂, Tr = 6.7 minutes) LRMS (ESI) Calc'd for C₃₀H₃₆F₃N₆O₄ [M + H]⁺: 601, found 601. 5-287

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-2- (trifluoromethyl)piperidin-2- yl)phenyl)amino)-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A. Derived from free pyridone Peak 2 via SFC: ID, 30% iPrOH + 0.25% DMEA in CO₂, Tr = 8.3 minutes) LRMS (ESI) Calc'd for C₃₀H₃₆F₃N₆O₄ [M + H]⁺: 601, found 601. 5-288

tert-butyl 4-(cyanomethyl)- 4-(3-((4-(N- isopropylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₇H₃₆N₇O₅S [M + H]⁺: 570, found 570. 5-289

tert-butyl 4-(3-((4-(N- benzylsulfamoyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)-4-(cyanomethyl) piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₆H₂₈N₇O₃S [M − Boc + H]⁺: 518, found 518. 5-290

tert-butyl 4-(cyanomethyl)- 4-(3-((4-(N- (cyclopropylmethyl) sulfamoyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₃H₂₈N₇O₃S [M − Boc + H]⁺: 482, found 482. 5-291

tert-butyl 4-(cyanomethyl)- 4-(3-((4-(N-(2- methoxyethyl)sulfamoyl) phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₂H₂₈N₇O₄S [M − Boc + H]⁺: 486, found 486. 5-292

tert-butyl 4-(cyanomethyl)- 4-(3-((4-(N- cyclohexylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₀H₄₀N₇O₅S [M + H]⁺: 610, found 610. 5-293

tert-butyl 4-(cyanomethyl)- 4-(4-oxo-3-((4-(piperidin-1- ylsulfonyl)phenyl)amino)- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₉H₃₈N₇O₅S [M + H]⁺: 596, found 596. 5-294

tert-butyl 4-(cyanomethyl)- 4-(3-((4- (morpholinosulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₈H₃₆N₇O₆S [M + H]⁺: 598, found 598. 5-295

tert-butyl 4-(cyanomethyl)- 4-(3-((3-fluoro-4-(N- isopropylsulfamoyl)phenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₇H₃₄FN₇O₅SNa [M + Na]⁺: 610, found 610. 5-296

tert-butyl 4-(cyanomethyl)- 4-(3-((4-(N- (cyclopropylmethyl) sulfamoyl)-3- fluorophenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1-carboxylate LRMS (ESI) calc'd for C₂₈H₃₄FN₇O₅SNa [M + Na]⁺: 622, found 622.

Example 6 (4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl)acetonitrile

Step 1: (4-{4-(benzyloxy)-3-[(4-fluorophenyl)amino]-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl)acetonitrile

To a solution of tert-butyl 4-{4-(benzyloxy)-3-[(4-fluorophenyl)amino]-1H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate (Example 5-48, step 1) (32 mg, 0.057 mmol) in CH₂Cl₂ (1 mL) was added TFA (0.10 mL, 1.3 mmol). The reaction was stirred at room temperature for 30 minutes, diluted with EtOAc, and then washed with 1N NaOH and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude title compound was used as is in the next step. LRMS (ESI) calc'd for C₂₆H₂₆FN₆O [M+H]⁺: 457. found 457.

Step 2: (4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl)acetonitrile (6)

To a solution of crude (4-{4-(benzyloxy)-3-[(4-fluorophenyl)amino]-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl)acetonitrile (28 mg, 0.061 mmol) in EtOAc (0.5 mL) and EtOH (0.5 mL) was added 10% wt. Pd/C (5 mg). The reaction was placed under 1 atmosphere of hydrogen and stirred vigorously at room temperature for 2 hours. The hydrogen atmosphere was removed and then the catalyst was removed by filtration through Celite. The filtrate was concentrated in vacuo and the residue was purified by mass triggered reverse phase HPLC, eluting with acetonitrile/water containing 0.1% TFA modifier. Fractions containing desired product were lyophilized to afford compound 7 as the TFA salt. LRMS (ESI) calc'd for C₁₉H₂₀FN₆O [M+H]⁺: 367. found 367. ¹H NMR (600 MHz, DMSO-d6): δ 11.35 (d, J=6.0 Hz, 1H), 8.40-8.55 (m, 2H), 8.20 (s, 1H), 7.63 (m, 2H), 7.21 (t, J=6.6 Hz, 1H), 7.07 (t, J=8.4 Hz, 2H), 6.66 (d, J=7.2 Hz, 1H), 3.26-3.34 (m, 4H), 2.97 (m, 2H), 2.82 (m, 2H), 2.19 (m, 2H).

Example 7 [1-(cyclopropylcarbonyl)-4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl]acetonitrile

Step 1: [4-{4-(benzyloxy)-3-[(4-fluorophenyl)amino]-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-(cyclopropylcarbonyl)piperidin-4-yl]acetonitrile

To a solution of crude (4-{4-(benzyloxy)-3-[(4-fluorophenyl)amino]-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl)acetonitrile (Example 6, Step 1) (21 mg, 0.046 mmol) in CH₂Cl₂ (1.0 mL) was added DIPEA (24.0 μL, 0.138 mmol) followed by cyclopropanecarbonyl chloride (6.3 μL, 0.069 mmol). The reaction was stirred at room temperature for 30 minutes and then diluted with EtOAc and washed with saturated aqueous NaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification of the residue using silica chromatography, eluting with 0-100% EtOAc in hexanes afforded the title compound. LRMS (ESI) calc'd for C₃₀H₃₀FN₆O₂[M+H]⁺: 525. found 525.

Step 2: [1-(cyclopropylcarbonyl)-4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl]acetonitrile (7)

To a solution of [4-{4-(benzyloxy)-3-[(4-fluorophenyl)amino]-1H-pyrazolo[4,3-c]pyridin-1-yl}-1-(cyclopropylcarbonyl)piperidin-4-yl]acetonitrile (12 mg, 0.024 mmol) in EtOAc (1.5 mL) and EtOH (0.5 mL) was added Pd/C (5.0 mg, 10% wt.). The reaction was placed under 1 atmosphere of hydrogen and stirred vigorously at room temperature for 2 hours. The hydrogen atmosphere was removed and the reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography, eluting with 0-5% MeOH in EtOAc to afford compound 7. LRMS (ESI) calc'd for C₂₃H₂₄FN₆O₂ [M+H]⁺: 435. found 435. ¹H NMR (600 MHz, CD₃OD): δ 8.06 (s, 1H), 7.60 (m, 2H), 7.19 (d, J=7.2 Hz, 1H), 7.01 (t, J=8.4 Hz, 2H), 6.73 (d, J=7.8 Hz, 1H), 5.47 (s, 1H), 4.25 (m, 2H), 3.51 (m, 1H), 3.14 (s, 2H), 2.86-3.15 (m, 3H), 1.95-2.18 (m, 3H), 0.74-0.90 (m, 4H).

Example 8-1 4-({1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide

Step 1: 3-((4-(benzyloxy)-1-(4-(cyanomethyl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide

To a solution of tert-butyl 4-(4-(benzyloxy)-3-((3-(N,N-dimethylsulfamoyl) phenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (5-1a) (3.50 g, 5.42 mmol) in CH₂Cl₂ (46 mL) at 0° C., was added tetrafluoroboric acid-diethyl ether complex (1.55 mL, 11.4 mmol). The reaction mixture was stirred and warmed to room temperature over 4 hours. The reaction was quenched with saturated aqueous NaHCO₃, and diluted with CH₂Cl₂. The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (×3). The combined organics were washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo to afford the title compound as a solid. ¹H NMR (500 MHz, CDCl₃): δ 7.93 (d, J=6.5 Hz, 1H), 7.73-7.70 (m, 3H), 7.56-7.44 (m, 6H), 6.98 (d, J=6.5 Hz, 1H), 5.60 (s, 2H), 3.21-3.10 (m, 2H), 3.02-2.96 (m, 6H), 2.69 (s, 6H), 2.28-2.24 (m, 2H).

Step 2: 4-({1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,Ndimethylbenzenesulfonamide (8-1)

An oven dried reaction vessel was charged with 3-((4-(benzyloxy)-1-(4-(cyanomethyl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide (20 mg, 0.037 mmol), DMF (0.19 mL, 0.2 M), benzaldehyde (3.8 mg, 0.037 mmol), TFA (18.8 mg, 0.165 mmol), and triacetoxyborohydride (39 mg, 0.183 mmol). The reaction vessel was sealed and heated to 50° C. overnight. Upon cooling to room temperature, HCl in dioxane (0.10 mL, 2M) was added, and the reaction mixture was stirred for an additional 4 hours. The crude reaction mixture was filtered and purified using mass directed reverse phase column chromatography to afford Example 8-1. LRMS (ESI) calc'd for C₂₈H₃₂N₇O₃S [M+H]⁺: 546. found 546. ¹H NMR (600 MHz, DMSO-d6): δ 11.31 (s, 1H) 8.68 (s, 1H), 7.83 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 7.26 (m, 3H), 7.18 (m, 1H), 7.16 (m, 1H), 6.67 (m, 1H), 6.51 (m, 1H), 3.71 (br s, 1H), 2.65 (d, 2H), 2.54 (s, 6H), 2.08 (m, 1H), 1.36 (s, 2H).

The following compounds in Table 21 were prepared in analogy to Example 8-1 above.

TABLE 21 Example Structure Compound Name LRMS 8-2 

4-({1-[4-(cyanomethyl)-1-(4- methylbenzyl)piperidin-4-yl]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₉H₃₄N₇O₃S [M + H]⁺: 560, found 560. 8-3 

4-[(1-{4-(cyanomethyl)-1-[4- (trifluoromethyl) benzyl]piperidin-4-yl}-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino]-N,N- dimethyl benzenesulfonamide LRMS (ESI) calc'd for C₂₉H₃₁F₃N₇O₃S [M + H]⁺: 614, found 614. 8-4 

4-[(1-{4-(cyanomethyl)-1[4-(1- methylethyl) benzyl]piperidin-4-yl}-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino]-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc' d for C₃₁H₃₈N₇O₃S [M + H]⁺: 588, found 588. 8-5 

4-[(1-{4-(cyanomethyl)-1-[4-(1- methylethyl)benzyl] piperidin-4-yl}-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino]-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₉H₃₁N₈O₃S [M + H]⁺: 571, found 571. 8-6 

4-[(1-{4-(cyanomethyl)-1-[4- (1methylethoxy)benzyl] piperidin-4-yl}-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino]-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₃₁H₃₈N₇O₄S [M + H]⁺: 604, found 604. 8-7 

4-({1-[4-(cyanomethyl)-1-(4- fluorobenzyl)piperidin-4-yl]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N-dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₈H₃₁FN₇O₃S [M + H]⁺: 564, found 564. 8-8 

4-({1-[4-(cyanomethyl)-1-(3- fluorobenzyl)piperidin-4-yl]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N-dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₈H₃₁FN₇O₃S [M + H]⁺: 564, found 564. 8-9 

4-({1-[4-(cyanomethyl)-1-(2- fluorobenzyl)piperidin-4-yl]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N-dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₈H₃₁FN₇O₃S [M + H]⁺: 564, found 564. 8-10

4-({1-[4-(cyanomethyl)-1-(2,6- difluorobenzyl) piperidin-4-yl]- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N-dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₈H₃₀F₂N₇O₃S [M + H]⁺: 582, found 582. 8-11

4-({1-[4-(cyanomethyl)-1-(2,3,6- trifluorobenzyl) piperidin-4-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl}amino)-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₈H₂₉F₃N₇O₃S [M + H]⁺: 600, found 600. 8-12

4-({1-[4-(cyanomethyl)-1-(1,3- oxazol-2-ylmethyl) piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N-dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₅H₂₉N₈O₄S [M + H]⁺: 537, found 537. 8-13

4-({1-[4-(cyanomethyl)-1-(4- isoxazol-3-ylbenzyl) piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N-dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₃₁H₃₃N₈O₄S [M + H]⁺: 613, found 613. 8-14

4-[(1-{4-(cyanomethyl)-1-[4-(2- oxopyrrolidin-1-yl)benzyl] piperidin-4-yl}-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino]-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₃₂H₃₇N₈O₄S [M + H]⁺: 629, found 629. 8-15

4-({1-[4-(cyanomethyl)-1-(3- phenylpropyl)piperidin-4-yl]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N-dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₃₀H₃₆N₇O₃S [M + H]⁺: 574, found 574. 8-16

4-({1-[4-(cyanomethyl)-1-(1H- indol-4-ylmethyl) piperidin-4-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl}amino)-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₃₀H₃₃N₈O₃S [M + H]⁺: 585, found 585. 8-17

4-((1-(4-(cyanomethyl)-1-(1- (2,6-difluorophenyl) ethyl)piperidin-4-yl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- dimethyl benzenesulfonamide LRMS (ESI) calc'd for C₂₉H₃₂F₂N₇O₃S [M + H]⁺: 596, found 596. 8-18

4-((1-(4-(cyanomethyl)-1- phenethylpiperidin-4-yl)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₉H₃₄N₇O₃S [M + H]⁺: 560, found 560. 8-19

3-({1-[4-(cyanomethyl)-1- (pyridin-3-ylmethyl) piperidin-4-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl}amino)-N,N- dimethylbenzene sulfonamide LRMS (ESI) calc'd for C₂₇H₃₁N₈O₃S [M + H]⁺: 547, found 547.

Example 9-1 4-({1-[4-(cyanomethyl)-1-propanoylpiperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide

An oven dried reaction vessel was charged with PS-CDI (97 mg, 0.137 mmol) and DMF (0.55 mL, 0.1 M), and was shaken for 5 minutes. To this suspension, HOBt (11 mg, 0.082 mmol), 3-((4-(benzyloxy)-1-(4-(cyanomethyl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide (Example 8-1, Step 1) (30 mg, 0.055 mmol), and propionic acid (4.1 mg, 0.055 mmol) were added followed by DIPEA (14 mg, 0.11 mmol). The reaction mixture was stirred at room temperature overnight, then HCl in dioxane (0.20 mL, 2M) was added, and the reaction mixture was stirred at room temperature for an additional 2 hours. To this reaction mixture, Si-Carbonate (250 mg, 0.11 mmol) and additional DMF (1.0 mL) were added. The reaction was stirred overnight at room temperature. The reaction mixture was filtered, and the crude material containing compound 9-1 was purified using mass directed reverse phase column chromatography. LRMS (ESI) calc'd for C₂₄H₃₀N₇O₄S [M+H]⁺: 512. found 512. ¹H NMR (600 MHz, DMSO-d6): δ 11.33 (d, J=5.9 Hz, 1H), 8.68 (s, 1H), 7.83 (d, J=8.6 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.19 (t, J=6.7 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 4.00 (m, 1H), 3.73 (m, 1H), 3.29-3.23 (m, 3H), 3.05-3.01 (m, 1H), 2.69-2.65 (m, 2H), 2.54 (s, 6H), 2.34-2.30 (m, 2H), 2.05 (m, 1H), 1.96 (m, 1H), 0.94 (t, J=7.4 Hz, 3H).

The following compounds in Table 22 were prepared in analogy to Example 9-1.

TABLE 22 Example Structure Compound Name LRMS 9-2 

4-({1-[4-(cyanomethyl)-1- (3,3,3- trifluoropropanoyl)piperidin- 4-yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₄H₂₇F₃N₇O₄S [M + H]⁺: 566, found 566. 9-3 

4-({1-[4-(cyanomethyl)-1- (methoxyacetyl)piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₄H₃₀N₇O₅S [M + H]⁺: 528, found 528. 9-4 

4-({1-[4-(cyanomethyl)-1- (N,N- dimethylglycyl)piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₅H₃₃N₈O₄S [M + H]⁺: 541, found 541. 9-5 

4-({1-[4-(cyanomethyl)-1- (2,2- dimethylpropanoyl)piperidin- 4-yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₆H₃₄N₇O₄S [M + H]⁺: 540, found 540. 9-6 

4-({1-[4-(cyanomethyl)-1- (cyclopropylcarbonyl)piperidin- 4-yl]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₆H₃₀N₇O₄S [M + H]⁺: 524, found 524. 9-7 

4-[(1-{4-(cyanomethyl)-1- [(3,3- difluorocyclobutyl)carbonyl] piperidin-4-yl}-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino]-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₆H₃₀F₂N₇O₄S [M + H]⁺: 574, found 574. 9-8 

4-({1-[4-(cyanomethyl)-1- (cyclohexylcarbonyl)piperidin- 4-yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₈H₃₆N₇O₄S [M + H]⁺: 566, found 566. 9-9 

4-[(1-{4-(cyanomethyl)-1- [(3S,5S,7S)- tricyclo[3.3.1.1^(3,7)]dec-1- ylcarbonyl]piperidin-4-yl}-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino]-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₃₂H₄₀N₇O₄S [M + H]⁺: 618, found 618. 9-10

4-({1-[4-(cyanomethyl)-1- (cyclopropylacetyl)piperidin- 4-yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₆H₃₂N₇O₄S [M + H]⁺: 538, found 538. 9-11

4-({1-[4-(cyanomethyl)-1-(3- cyclopropylpropanoyl)piperidin- 4-yl]-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₇H₃₄N₇O₄S [M + H]⁺: 552, found 552. 9-12

4-({1-[4-(cyanomethyl)-1- (phenylcarbonyl)piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₈H₃₀N₇O₄S [M + H]⁺: 560, found 560. 9-13

4-[(1-{1-[(4- chlorophenyl)carbonyl]-4- (cyanomethyl)piperidin-4-yl}- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino]-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₈H₂₉ClN₇O₄S [M + H]⁺: 594, found 594. 9-14

4-[(1-{1-[(3- chlorophenyl)carbonyl]-4- (cyanomethyl)piperidin-4-yl}- 4-oxo-4,5-dihydro-1H- pyrazolo [4,3-c]pyridin-3-yl)amino]- N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₈H₂₉ClN₇O₄S [M + H]⁺: 594, found 594. 9-15

4-[(1-{1-[(2- chlorophenyl)carbonyl]-4- (cyanomethyl)piperidin-4-yl}- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino]-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₈H₂₉ClN₇O₄S [M + H]⁺: 594, found 594. 9-16

4-({1-[4-(cyanomethyl)-1- {[4- (trifluoromethyl)phenyl]acetyl} piperidin-4-yl]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₃₀H₃₁F₃N₇O₄S [M + H]⁺: 642, found 642. 9-17

4-({1-[4-(cyanomethyl)-1-(3- phenylpropanoyl)piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₃₀H₃₄N₇O₄S [M + H]⁺: 588, found 588. 9-18

4-({1-[4-(cyanomethyl)-1- (2,3-dihydro-1H-inden-2- ylcarbonyl)piperidin-4-yl]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₃₁H₃₄N₇O₄S [M + H]⁺: 600, found 600. 9-19

4-[(1-{4-(cyanomethyl)-1-[(2- oxopyrrolidin-1- yl)acetyl]piperidin-4-yl}-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino]-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₇H₃₃N₈O₅S [M + H]⁺: 581, found 581. 9-20

4-({1-[4-(cyanomethyl)-1- (tetrahydro-2H-pyran-4- ylcarbonyl)piperidin-4-yl]-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₇H₃₄N₇O₅S [M + H]⁺: 568, found 568. 9-21

4-({1-[4-(cyanomethyl)-1- (4,4,4- trifluorobutanoyl)piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₅H₂₉F₃N₇O₄S [M + H]⁺: 580, found 580. 9-22

4-({1-[4-(cyanomethyl)-1-(3- cyanopropanoyl)piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₅H₂₉N₈O₄S [M + H]⁺: 537, found 537. 9-23

4-({1-[4-(cyanomethyl)-1- (3,3- dimethylbutanoyl)piperidin-4- yl]-4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl}amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₇H₃₆N₇O₄S [M + H]⁺: 554, found 554. 9-24

4-((1-(4-(cyanomethyl)-1-(2- (methylthio)propanoyl)piperidin- 4-yl)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-3- yl)amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₅H₃₂N₇O₄S₂ [M + H]⁺: 558, found 558. 9-25

4-((1-(1-(2-cyanoacetyl)-4- (cyanomethyl)piperidin-4-yl)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-3- yl)amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₄H₂₇N₈O₄S [M + H]⁺: 523, found 523.

Example 10-1 methyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

To a solution of 3-((4-(benzyloxy)-1-(4-(cyanomethyl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide (Example 8-1, Step 1) (25 mg, 0.046 mmol), in CH₂Cl₂ (0.2 M), was added 2,6-lutidine (12.3 mg, 0.115 mmol). The reaction mixture was cooled to 0° C. and methyl chloroformate (4.76 mg, 0.050 mmol) was added. The reaction was stirred to room temperature until the reaction was judged complete by LCMS, at which point it was cooled to 0° C. and 0.2 mL of TFA was added. The reaction mixture was filtered and purified using mass directed reverse phase chromatography. LRMS (ESI) calc'd for C₂₃H₂₈N₇O₅S [M+H]⁺: 514. found 514. ¹H NMR (600 MHz, DMSO-d6): δ 11.33 (d, J=5.9 Hz, 1H), 8.71 (s, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.19 (m, 1H), 6.70 (m, 1H), 3.82-3.78 (m, 2H), 3.58 (s, 3H), 3.31 (m, 1H), 3.29 (m, 1H), 3.21-3.13 (m, 1H), 2.72-2.64 (m, 1H), 2.57 (s, 6H), 2.48-2.44 (m, 2H), 2.10-2.02 (m, 2H).

The following compounds in Table 23 were prepared in analogy to that of Example 10-1.

TABLE 23 Example Structure Compound Name LRMS 10-2

phenyl 4-(cyanomethyl)- 4-(3-((4-(N,N- dimethylsulfamoyl) phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₈H₃₀N₇O₅S [M + H]⁺: 576, found 576. 10-3

4-fluorophenyl 4- (cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₈H₂₉FN₇O₅S [M + H]⁺: 594, found 594. 10-4

neopentyl 4- (cyanomethyl)-4-(3-((4- (N,N- dimethylsulfamoyl)phenyl) amino)-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₇H₃₆N₇O₅S [M + H]⁺: 570, found 570. 10-5

ethyl 4-(cyanomethyl)-4- (3-((4-(N,N- dimethylsulfamoyl) phenyl)amino)-4-oxo- 4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₄H₃₀N₇O₅S [M + H]⁺: 528, found 528. 10-6

isopropyl 4- (cyanomethyl)-4-(3-((4- (N,N- dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₅H₃₂N₇O₅S [M + H]⁺: 542, found 542.

Example 11-1 methyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

To a DMSO solution (0.5 M) of triethylamine (46 mg, 0.45 mmol) and 2-methoxy ethanol (11 mg, 0.15 mmol) was added N,N′-disuccinimidyl carbonate (38 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 4 hours then a DMSO (0.5 M) solution of 3-((4-(benzyloxy)-1-(4-(cyanomethyl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide (Example 8-1, Step 1) (41 mg, 0.075 mmol) was added. The reaction mixture was stirred at room temperature overnight, then quenched by addition of TFA (0.10 mL) and then neutralized after benzyl ether cleavage by addition of PS-Carbonate (300 mg). The reaction was filtered and purified using mass directed reverse phase chromatography to afford compound 11-1. LRMS (ESI) calc'd for C₂₅H₃₂N₇O₆S [M+H]⁺: 558. found 558. ¹H NMR (600 MHz, DMSO-d6): δ 11.31 (d, J=5.9 Hz, 1H), 8.71 (s, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.19 (m, 1H), 6.70 (m, 1H), 3.85-3.65 (m, 4H), 3.47-3.37 (m, 4H), 3.32 (s, 3H), 2.72-2.64 (m, 2H), 2.57 (s, 6H), 2.10-2.02 (m, 2H), 1.85-1.75 (m, 2H).

The following compounds in Table 24 were prepared in an analogous manner to that of Example 11-1.

TABLE 24 Example Structure Compound Name LRMS 11-2 

(trans racemic)-2- methylcyclopentyl 4- (cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₈H₃₆N₇O₅S [M + H]⁺: 582, found 582. 11-3 

2-(methylthio)ethyl 4- (cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₅H₃₂N₇O₅S₂ [M + H]⁺: 574, found 574. 11-4 

tetrahydro-2H-thiopyran- 4-yl 4-(cyanomethyl)-4- (3-((4-(N,N- dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₇H₃₄N₇O₅S₂ [M + H]⁺: 600, found 600. 11-5 

1-methoxypropan-2-yl 4- (cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₄N₇O₆S [M + H]⁺: 572, found 572. 11-6 

(R)-tetrahydrofuran-3-yl 4-(cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₂N₇O₆S [M + H]⁺: 570, found 570. 11-7 

tetrahydro-2H-pyran-4-yl 4-(cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₇H₃₄N₇O₆S [M + H]⁺: 584, found 584. 11-8 

1,1,1-trifluoropropan-2-yl 4-(cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₅H₂₉F₃N₇O₅S [M + H]⁺: 596, found 596. 11-9 

1-(pyridin-2-yl)ethyl 4- (cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₉H₃₃N₈O₅S [M + H]⁺: 605, found 605. 11-10

1-cyanoethyl 4- (cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₅H₂₉N₈O₅S [M + H]⁺: 553, found 553. 11-11

(S)-tetrahydrofuran-3-yl 4-(cyanomethyl)-4-(3-((4- (N,N-dimethylsulfamoyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₂₆H₃₂N₇O₆S [M + H]⁺: 570, found 570.

Example 12 2,2,2-trifluoroethyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

To a solution of 4-((1-(4-(cyanomethyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethyl benzenesulfonamide (Example 8-1, Step 1) (82 mg, 0.25 mmol) in DMF (1.0 mL) was added 2,2,2-trifluoroethanol (50 mg, 0.50 mmol) and Et₃N (50 mg, 0.50 mmol). The solution was cooled to −20° C., then triphosgene (4.0 mg, 1.3 mmol) was added and the resulting solution was stirred at −20° C. for 4 hours. The mixture was filtered, and the filtrate was concentrated in vacuo and purified by reverse phase HPLC using water/acetonitrile with 0.225% formic acid modifier to give compound 12 as a solid. LRMS (ESI) calc'd for C₂₄H₂₇F₃N₇O₅S [M+H]⁺: 582. found 582. ¹H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 8.72 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.66-7.64 (m, 2H), 7.24-7.21 (m, 1H), 6.74 (d, J=7.6 Hz, 1H), 4.71-4.69 (m, 2H), 3.86-3.82 (m, 2H), 3.28 (s, 2H), 2.73-2.73 (m, 2H), 2.59 (s, 6H), 2.13-1.97 (m, 4H).

Example 13-1 isopropyl-4-(cyanomethyl)-4-(3-(2-fluoropyridin-4-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate

Step 1: tert-butyl 4-(4-(benzyloxy)-3-((2-fluoropyridin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

To tert-butyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (0.20 g, 0.44 mmol), 4-bromo-2-fluoropyridine (93 mg, 0.54 mmol), di-tert-butyl (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (37 mg, 0.090 mmol), tris(dibenzylideneacetone) dipalladium(0) chloroform adduct (46 mg, 0.050 mmol) and potassium acetate (88 mg, 0.90 mmol), was added isopropanol (30 mL). The mixture was degassed by purging with nitrogen and then heated to 80° C. for 6 hours. The solution was cooled and water (10 mL) was added. The mixture was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine (×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica chromatography, eluting with ethyl acetate/petroleum ether (1/3) to afford the title compound as a solid. LRMS (ESI) calc'd for C₃₀H₃₃FN₇O₃[M+H]⁺: 558. found 558.

Step 2: 2-(4-(3-((2-fluoropyridin-4-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile

To a solution of tert-butyl 4-(4-(benzyloxy)-3-(2-fluoropyridin-4-ylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (0.21 g, 0.37 mmol) in dichloromethane (20 mL), was added TFA (0.42 g, 3.70 mmol). The reaction mixture was stirred for 2 hours at ambient temperature, then concentrated in vacuo to afford a solid that was used as is in the next step. LRMS (ESI) calc'd for C₁₈H₁₉FN₇O [M+H]⁺: 368. found 368.

Step 3: isopropyl-4-(cyanomethyl)-4-(3-(2-fluoropyridin-4-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (13-1)

To a solution of 2-(4-(3-(2-fluoropyridin-4-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl) acetonitrile (30 mg, 0.06 mmol) in methanol (5 mL) was added isopropyl chloroformate (9 mg, 0.07 mmol) and sodium carbonate (20 mg, 0.18 mmol). The mixture was stirred for 2 hours at ambient temperature, then cooled and quenched by addition of water (10 mL). The mixture was extracted with ethyl acetate (×2) and the combined organic layers were washed with brine (×2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase chromatography, using water (with 0.05% ammonium bicarbonate modifier) and acetonitrile. Desired fractions were concentrated in vacuo to afford a solid. LCMS (ESI) calc'd for C₂₂H₂₅FN₇O₃[M+H]⁺: 454. found 454; ¹H NMR (400 MHz, DMSO-d₆): δ 11.40 (br s, 1H), 9.02 (s, 1H), 7.97 (d, J=6.0 Hz, 1H), 7.52 (d, J=6.0 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.25-7.21 (m, 1H), 6.73 (d, J=7.5 Hz, 1H), 4.77 (m, 1H) 3.78 (m, 2H), 3.18 (m, 2H), 2.67 (m, 2H), 2.50 (m, 2H), 2.11-2.05 (m, 2H), 1.18 (d, J=8.0 Hz, 6H).

The following examples in Table 25 were prepared in an analogous manner as outlined above, using an appropriate chloroformate reagent.

TABLE 25 Example Structure Compound Name LRMS 13-2

methyl 4-(cyanomethyl)-4- (3-(2-fluoropyridin-4- ylamino)-4-oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₂₀H₂₁FN₇O₃ [M + H]⁺: 426, found 426.

Example 14-1 4-((1-(4-(cyanomethyl)-1-((2,2,2-trifluoroethyl)sulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N- dimethylbenzenesulfonamide

To a CH₂Cl₂ solution (0.51 mL, 0.1 M) of 2,6-lutidine (28 mg, 0.257 mmol) and 3-((4-(benzyloxy)-1-(4-(cyanomethyl)piperidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide (Example 8-1, Step 1) (28 mg, 0.051 mmol), 2,2,2-trifluoroethanesulfonyl chloride (12 mg, 0.063 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours followed by the addition of TFA (0.2 mL). The reaction mixture was stirred at room temperature for an additional 4 hours. The reaction was quenched with PS-Carbonate (250 mg), filtered, and purified using mass directed reverse phase column chromatography to afford compound 14-1. LRMS (ESI) calc'd for C₂₃H₂₇F₃N₇O₅S₂ [M+H]+⁺: 602. found 602. ¹H NMR (500 MHz, DMSO-d6): δ 11.31 (d, J=5.9 Hz, 1H), 8.71 (s, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.19 (m, 1H), 6.70 (m, 1H), 4.49-4.41 (m, 2H), 3.75-3.65 (m, 2H), 3.47-3.37 (m, 2H), 3.30-3.23 (m, 2H), 2.89-2.82 (m, 2H), 2.57 (s, 6H), 2.24-2.12 (m, 2H).

The following compound in Table 27 was prepared in an analogous manner to that of Example 14-1:

TABLE 27 Example Structure Compound Name LRMS 14-2

4-((1-(4-(cyanomethyl)-1- (cyclopropylsulfonyl)piperidin- 4-yl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₄H₃₀N₇O₅S₂ [M + H]⁺: 560, found 560.

Example 15-1 2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile

Step 1: tert-butyl 4-(4-(benzyloxy)-3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

To a suspension of tert-butyl 4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (0.69 g, 1.5 mmol) and KOAc (200 mg, 2.04 mmol) in i-PrOH (4.0 mL) was added 4-bromophenyl methyl sulfone (0.47 g, 2.0 mmol) followed by Pd₂(dba)₃ (140 mg, 0.153 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (60 mg, 0.15 mmol) under nitrogen. The resulting suspension was heated to 105° C. by microwave for 1 hour. The mixture was then cooled to room temperature and filtered. The filtrate was purified by preparative TLC, eluting with 50% EtOAc in hexanes, to give the title compound as a solid. LRMS (ESI) calc'd for C₃₂H₃₇N₆O₅S [M+H]⁺: 617. found 617. ¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, J=6.4 Hz, 1H), 7.86 (d, J=7.2 Hz, 2H), 7.76 (br s, 1H), 7.56-7.42 (m, 7H), 6.99 (d, J=6.4 Hz, 1H), 5.61 (s, 2H), 4.10-3.92 (m, 2H), 3.21-3.10 (m, 2H), 3.04 (s, 3H), 2.99-2.95 (m, 2H), 2.92 (s, 2H), 2.14-2.08 (m, 2H), 1.49 (s, 9H).

Step 2: 2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl) acetonitrile (HCl salt)

To a suspension of tert-butyl 4-(4-(benzyloxy)-3-((4-(methylsulfonyl) phenyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl) piperidine-1-carboxylate (160 mg, 0.260 mmol) in EtOAc (2 mL) was added HCl (2 mL, 4M in EtOAc, 8 mmol). The resulting suspension was stirred for 4 hours at room temperature. The mixture was then filtered, and the solid was washed with EtOAc and dried to afford the title compound as the HCl salt. LRMS (ESI) calc'd for C₂₀H₂₃N₆O₃S [M+H]: 427. found 427. ¹H NMR (400 MHz, DMSO-d6): δ 11.46 (d, J=5.6 Hz, 1H), 8.90 (br s, 2H), 8.77 (s, 1H), 7.87 (d, J=8.8 Hz, 4H), 7.80 (d, J=9.2 Hz, 2H), 7.30-7.26 (m, 1H), 6.79 (d, J=7.6 Hz, 2H), 3.34-3.29 (m, 2H), 3.27 (s, 2H), 3.12 (s, 3H), 3.04-2.98 (m, 2H), 2.91-2.88 (m, 2H), 2.30-2.25 (m, 2H).

Step 3: 6-(4-(cyanomethyl)-4-(3-((4-((difluoromethyl)sulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl) nicotinonitrile

To a solution of 2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile (0.10 g, 0.24 mmol) in DMF (1.0 mL) was added 2-chloro-4-(trifluoromethyl)pyridine (56 mg, 0.31 mmol) and DIPEA (61 mg, 0.48 mmol). The reaction was sealed and heated to 120° C. for 16 hours, then cooled and filtered and the filtrate was purified by reverse phase HPLC. LRMS (ESI) calc'd for C₂₆H₂₅N₇O₃SF₃ [M+H]⁺: 572. found 572. ¹H NMR (400 MHz, DMSO-d6): δ 11.41 (br s, 1H), 8.75 (s, H), 8.34 (d, J=4.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.28-7.23 (m, 1H), 7.15 (s, 1H), 6.86 (d, J=4.8 Hz), 6.75 (d, J=7.6 Hz, 1H), 4.18-4.09 (m, 2H), 3.44-3.28 (m, 4H), 3.16 (s, 3H), 2.81-2.72 (m, 2H), 2.18-2.04 (m, 2H).

Following analogous procedures to that outlined for Example 15-1 above, the following compounds in Table 28 were prepared. In certain instances the Boc deprotection (Step 2) could be achieved on the free pyridone compound of the type depicted in Example 5 shown in Table 20 using TFA in DCM at room temperature prior to the S_(N)Ar reaction. In certain instances the S_(N)Ar reaction could be conducted using alternate suitable bases, such as TEA for example, typically at temperatures >80° C.

TABLE 28 Example Structure Compound Name LRMS 15-2

6-(4-(cyanomethyl)-4-(3- ((4(methylsulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidin- 1-yl)nicotinonitrile LRMS (ESI) calc'd for C₂₆H₂₅N₈O₃S [M + H]⁺: 529, found 529. 15-3

6-(4-(cyanomethyl)-4-(3- ((4((difluoromethyl) sulfonyl)phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidin-1- yl)nicotinonitrile LRMS (ESI) calc'd for C₂₆H₂₃N₈O₃SF₂ [M + H]⁺: 565, found 565. 15-4

2-(4-(3-((4- (methylsulfonyl) phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-1-(5 (trifluoromethyl)pyridin- 2-yl)piperidin-4- yl)acetonitrile LRMS (ESI) calc'd for C₂₆H₂₅N₇O₃SF₃ [M + H]⁺: 572, found 572. 15-5

6-(4-(cyanomethyl)-4-(3- ((3-methyl-4- (thiomorpholine-4- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidin-1- yl)nicotinonitrile LRMS (ESI) Calc'd for C₃₁H₃₂N₉O₂S [M + H]⁺: 594, found 594. 15-6

6-((3R,4R)-4- (cyanomethyl)-3-fluoro-4- (3-((3-methyl-4- (thiomorpholine-4- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)piperidin-1- yl)nicotinonitrile (from I- 7-2B) LRMS (ESI) Calc'd for C₃₁H₃₁FN₉O₂S [M + H]⁺: 612, found 612. 15-7

2-(1-(5-iodopyridin-2-yl)- 4-(3-((4-(methylsulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidin- 4-yl)acetonitrile LRMS (ESI) calc'd for C₂₅H₂₅IN₇O₃S [M + H]⁺: 630, found 630. 15-8

2-(1-(5-bromopyridin-2- yl)-4-(3-((4- (methylsulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidin- 4-yl)acetonitrile LRMS (ESI) calc'd for C₂₅H₂₅BrN₇O₃S [M + H]⁺: 582, 584 (1:1), found 582, 584 (1:1).

Example 16-1 2-(4-(3-(3-methyl-4-(thiomorpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile

Step 1: 2-(4-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile hydrochloride

To tert-butyl4-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (0.50 g, 1.1 mmol) was added a solution of hydrogen chloride (80 mL, 160 mmol, 2M in EtOAc). The mixture was stirred for 6 hours at ambient temperature, then concentrated in vacuo to obtain the crude title compound that was used directly in the next step. LRMS (ESI) calc'd for C₁₃H₁₇N₆O [M+H]⁺: 273. found 273.

Step 2: 2-(4-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile

To a solution of 2-(4-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile hydrochloride (0.37 g, 1.2 mmol) in DMF (4 mL), was added 2-fluoro-4-(trifluoromethyl)pyridine (0.24 g, 1.4 mmol) and triethylamine (0.24 g, 2.4 mmol). The mixture was stirred for 4 hours at 110° C., then cooled and diluted with water and extracted with EtOAc (×2). The combined organic layers were washed with water (×2), brine (×2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica chromatography, eluting with 25% EtOAc in petroleum ether to afford the title compound as a solid. LRMS (ESI) calc'd for C₁₉H₁₉F₃N₇O [M+H]⁺: 418. found 418. ¹H NMR (400 MHz, DMSO-d₆): δ 10.95 (s, 1H), 8.33 (s, 1H), 7.19-7.13 (m, 1H), 7.09-7.01 (m, 1H), 6.88 (m, 1H), 6.56 (d, J=7.2 Hz, 1H), 5.46 (br s, 2H), 4.11 (m, 2H), 3.27-3.18 (m, 4H), 2.68 (m, 2H), 2.09-2.01 (m, 2H).

Step 3: 2-(4-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile

To a stirred solution of 2-(4-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile (30 mg, 0.070 mmol) in 2-propanol (10 mL) at ambient temperature under nitrogen, was added potassium acetate (14 mg, 0.14 mmol), tris(dibenzylideneacetonyl)bis-palladium(0) chloroform adduct (10 mg, 0.010 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (8 mg, 0.02 mmol) and (4-bromo-2-methylphenyl)(thiomorpholino)methanone (24 mg, 0.080 mmol). The reaction mixture was stirred at 80° C. for 4 hours, then cooled and quenched with water and extracted with EtOAc (×2). The combined organic layers were washed with brine (×2), dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The product was purified by reverse phase HPLC using water (with 0.05% NH₄HCO₃ modifier) and acetonitrile. The desired fractions were combined and concentrated in vacuo to the title compound as a solid. LCMS (ESI) calc'd for C₃₁H₃₂F₃N₈O₂S [M+H]⁺: 637. found 637. ¹H NMR (400 MHz, DMSO-d₆): δ 11.34 (br s, 1H), 8.35 (m, 1H), 8.27 (s, 1H), 7.58-7.50 (m, 2H), 7.24-7.13 (m, 3H), 6.88 (d, J=6.8 Hz, 1H), 6.72 (d, J=10.0 Hz, 1H), 4.17-4.29 (m, 2H), 3.88 (m, 2H), 3.46-3.37 (m, 2H), 3.30 (m, 4H), 2.79-2.67 (m, 6H), 2.27 (s, 3H), 2.21-2.01 (m, 2H).

Following analogous procedures to that outlined for Example 16-1 above, the following compounds in Table 29 were prepared.

TABLE 29 Example Structure Compound Name LRMS 16-2

(R or S)-2-(4-(4-oxo-3-(4- (2,2,2-trifluoro-1- hydroxyethyl)phenylamino)- 4,5-dihydropyrazolo[4,3- c]pyridin-1-yl)-1-(4- (trifluoromethyl)pyridin-2- yl)piperidin-4-yl)acetonitrile (Separated as free pyridone using chiral HPLC Chiralpak IA, hexane:EtOH = 40:60, Tr = 4.4 minutes) LRMS (ESI) calc'd for C₂₇H₂₄F₆N₇O₂ [M + H]⁺: 592, found 592. 16-3

(R or S)-2-(4-(4-Oxo-3-(4- (2,2,2-trifluoro-1- hydroxyethyl)phenylamino)- 4,5-dihydropyrazolo[4,3- c]pyridin-1-yl)-1-(4- (trifluoromethyl)pyridin-2- yl)piperidin-4-yl)acetonitrile (Separated as free pyridone using chiral HPLC Chiralpak IA, hexane:EtOH = 40:60, Tr = 15.2 minutes) LRMS (ESI) calc'd for C₂₇H₂₄F₆N₇O₂ [M + H]⁺: 592, found 592. 16-4

2-(4-(3-(4-(4,4- difluoropiperidine-1- carbonyl)-3- methylphenylamino)-4-oxo- 4,5-dihydropyrazolo[4,3- c]pyridin-1-yl)-1-(4- (trifluoromethyl)pyridin-2- yl)piperidin-4-yl)acetonitrile LRMS (ESI) calc'd for C₃₂H₃₂F₅N₈O₂ [M + H]⁺: 655, found 655.

Example 17 2-(1-(2,2-difluoropropanoyl)-4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4- yl)acetonitrile

To a suspension of 2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile (Example 15-1, Step 2) (0.10 g, 0.22 mmol) in DMF (2.0 mL) was added HATU (20 mg) and 2,2-difluoropropanoic acid (24 mg, 0.023 mmol). The resulting suspension was stirred for 4 hours at room temperature, then partitioned between water and DCM, and the organic phase was washed with brine and concentrated in vacuo. The residue was purified by reverse phase HPLC, eluting with water/acetonitrile with 0.225% formic acid modifier to obtain compound 17. LRMS (ESI) calc'd for C₂₃H₂₄F₂N₆O₄S [M+H]⁺: 519. found 519. ¹H NMR (400 MHz, DMSO-d6): δ 11.40 (d, J=4.4 Hz, 1H), 8.75 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.8 Hz, 2H), 7.26-7.22 (m, 1H), 6.75 (d, J=7.6 Hz, 1H), 4.13-4.02 (m, 2H), 3.45-3.40 (m, 2H), 3.31 (s, 2H), 3.15 (s, 3H), 2.88-2.77 (m, 2H), 2.16-2.12 (m, 2H), 1.86 (t, J=20 Hz, 3H).

Examples 18-1 and 18-2 (cis and trans) 2-(4-(3-fluoroazetidin-1-yl)-1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile

Step 1: 2-(4-oxo-1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile

To a suspension of 2-(8-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,4-dioxaspiro[4.5]decan-8-yl)acetonitrile (Example 5-83) (0.30 g, 0.63 mmol) in THF (3.2 mL) was added 2.0 M aqueous HCl (0.64 mL, 1.3 mmol). The reaction mixture was stirred at 75° C. for 2 hours, then the reaction was neutralized with aqueous 2M sodium carbonate. The reaction was then purified by silica chromatography, eluting with 0-6% MeOH in DCM to give the title compound. LRMS (ESI) calc'd for C₂₁H₁₉F₃N₅O₂ [M+H]⁺: 430. found 430. ¹H NMR (600 MHz, DMSO-d6): δ 11.34 (d, J=5.6 Hz, 1H), 8.59 (s, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.20 (dd, J=7.4, 5.9 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 3.30 (s, 2H), 3.00-2.94 (m, 2H), 2.40-2.28 (m, 6H).

Step 2: (cis and trans) 2-(4-(3-fluoroazetidin-1-yl)-1-(4-oxo-3-((4-(trifluoromethyl)phenyl) amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile

To a suspension of 2-(4-oxo-1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile (0.12 g, 0.27 mmol) in a mixture of THF (1.1 mL) and MeOH (1.1 mL) was added 3-fluoroazetidine hydrochloride (0.75 g, 0.67 mmol) and acetic acid (0.12 mL, 2.1 mmol). The reaction mixture was stirred at room temperature for 15 minutes then sodium cyanoborohydride (0.42 g, 0.67 mmol) was added and the reaction mixture was allowed to stir for an additional 30 minutes at room temperature. The reaction mixture was concentrated in vacuo to afford a residue that was purified by silica chromatography, eluting with 0.5-5% MeOH in DCM to give pure trans compound 18-1 (diastereomer 1). LRMS (ESI) calc'd for C₂₄H₂₅F₄N₆O [M+H]⁺: 489. found 489. ¹H NMR (600 MHz, DMSO-d6): δ 11.27 (d, J=5.6 Hz, 1H), 8.55 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.16-7.13 (m, 1H), 6.64 (d, J=7.6 Hz, 1H), 5.20-5.04 (m, 1H), 3.57-3.48 (m, 2H), 3.16 (s, 2H), 3.05-3.01 (m, 1H), 3.01-2.96 (m, 1H), 2.40-2.33 (m, 2H), 2.25-2.21 (m, 1H), 2.13 (t, J=10.0 Hz, 2H), 1.53-1.38 (m, 4H). Cis compound 18-2, (diastereomer 2) was subjected to subsequent purification by reverse phase chromatography using AcCN in water with 0.1% TFA modifier. The desired fractions were diluted with EtOAc and neutralized with saturated aqueous NaHCO₃ and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. LRMS (ESI) calc'd for C₂₄H₂₅F₄N₆O [M+H]⁺: 489. found 489. ¹H NMR (600 MHz, DMSO-d6): δ 11.27 (d, J=5.7 Hz, 1H), 8.56 (s, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.16 (dd, J=7.4, 5.9 Hz, 1H), 6.63 (d, J=7.5 Hz, 1H), 5.10-4.94 (m, 1H), 3.48-3.39 (m, 2H), 3.13 (s, 2H), 3.01-2.91 (m, 2H), 2.73 (d, J=13.7 Hz, 2H), 2.19-2.12 (m, 1H), 1.84-1.72 (m, 2H), 1.68 (dd, J=9.9, 3.9 Hz, 2H), 1.08-0.97 (m, 2H).

The following examples in Table 30 were prepared in an analogous fashion to that of Examples 18-1 and 18-2 above and relative stereochemistry was assigned by either NMR proof or by analogy based on biochemical activity. In the following examples, cis and trans stereochemistry refers to the relative orientation of the pyrrolopyrimidinone and amine substituents. In some cases, Step 1 of the sequence could be carried out using by substituting t-BuXphos ligand, i-PrOH and KOAc while using microwave irradiation.

TABLE 30 Example Structure Compound Name LRMS 18-3

Cis 2-(1-(4-oxo-3-((4- (trifluoromethyl)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl)-4-(phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₂₆F₃N₆O [M + H]⁺: 507, found 507. 18-4

Trans 2-(1-(4-oxo-3-((4- (trifluoromethyl)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl)-4-(phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₂₆F₃N₆O [M + H]⁺: 507, found 507. 18-5

(cis and trans) 2-(4-hydroxy-1- (4-oxo-3-((4-(trifluoromethyl) phenyl)amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₁H₂₁F₃N₅O₂ [M + H]⁺: 432, found 432. 18-6

Trans 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-(3- fluoroazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₃H₂₅ClFN₆O [M + H]⁺: 455, found 455. 18-7

Cis 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-(3- fluoroazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₃H₂₅ClFN₆O [M + H]⁺: 455, found 455. 18-8

Trans 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-(3- methoxyazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₂₈ClN₆O₂ [M + H]⁺: 467, found 467. 18-9

Cis 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-(3- methoxyazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₂₈ClN₆O₂ [M + H]⁺: 467, found 467. 18-10

Cis 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-((2,2,2- trifluoroethyl)amino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₂H₂₃ClF₃N₆O [M + H]⁺: 479, found 479. 18-11

Trans 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-((2,2,2- trifluoroethyl)amino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₂H₂₃ClF₃N₆O [M + H]⁺: 479, found 479. 18-12

Cis and trans 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- hydroxycyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₀H₂₁ClN₅O₂ [M + H]⁺: 398, found 398. 18-13

Cis 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₆H₂₆ClN₆O [M + H]⁺: 473, found 473. 18-14

Trans 2-(1-(3-((4- chlorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₆H₂₆ClN₆O [M + H]⁺: 473, found 473. 18-15

Cis 2-(4-(3-methoxyazetidin- 1-yl)-1-(4-oxo-3-((4- (trifluoromethoxy)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₅H₂₈F₃N₆O₃ [M + H]⁺: 517, found 517. 18-16

Trans 2-(4-(3- methoxyazetidin-1-yl)-1-(4- oxo-3-((4- (trifluoromethoxy)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₅H₂₈F₃N₆O₃ [M + H]⁺: 517, found 517. 18-17

Cis 2-(1-(4-oxo-3-((4- (trifluoromethoxy)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-4-(phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₂₆F₃N₆O₂ [M + H]⁺: 523, found 523. 18-18

Trans 2-(1-(4-oxo-3-((4- (trifluoromethoxy)phenyl) amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)-4-(phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₂₆F₃N₆O₂ [M + H]⁺: 523, found 523. 18-19

Trans 2-(4-(cyclohexylamino)- 1-(4-oxo-3-((4- (trifluoromethoxy) phenyl)amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₃₂F₃N₆O₂ [M + H]⁺: 529, found 529. 18-20

Cis 2-(4-(cyclohexylamino)- 1-(4-oxo-3-((4- (trifluoromethoxy) phenyl)amino)-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₃₂F₃N₆O₂ [M + H]⁺: 529, found 529. 18-21

Trans 2-(1-(3-((4-chloro-3- fluorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (cyclohexylamino)cyclohexyl) acetonitrile LRMS (ESI) calc'd for C₂₆H₃₁ClFN₆O [M + H]⁺: 497, found 497. 18-22

Cis 2-(1-(3-((4-chloro-3- fluorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (cyclohexylamino)cyclohexyl) acetonitrile LRMS (ESI) calc'd for C₂₆H₃₁ClFN₆O [M + H]⁺: 497, found 497. 18-23

Cis 2-(1-(3-((4-chloro-3- fluorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-(3- methoxyazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₂₇ClFN₆O₂ [M + H]⁺: 485, found 485. 18-24

Trans 2-(1-(3-((4-chloro-3- fluorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4-(3- methoxyazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₂₇ClFN₆O₂ [M + H]⁺: 485, found 485. 18-25

Cis 2-(1-(3-((4-chloro-3- fluorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₆H₂₅ClFN₆O [M + H]⁺: 491, found 491. 18-26

Trans 2-(1-(3-((4-chloro-3- fluorophenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-4- (phenylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₆H₂₅ClFN₆O [M + H]⁺: 491, found 491. 18-27

Cis 2-(1-(3-((4- ((difluoromethyl) sulfonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3- c]pyridin-1-yl)-4-(3- fluoroazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₂₆F₃N₆O₃S [M + H]⁺: 535, found 535. 18-28

Trans 2-(1-(3-((4- ((difluoromethyl)sulfonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo [4,3-c]pyridin-1- yl)-4-(3-fluoroazetidin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₂₆F₃N₆O₃S [M + H]⁺: 535, found 535. 18-29

Trans 4-((1-(1-(cyanomethyl)- 4-(3-fluoroazetidin-1- yl)cyclohexyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₅H₃₁N₇O₃FS [M + H]⁺: 528, found 528. 18-30

Cis 4-((1-(1-(cyanomethyl)-4- (3-fluoroazetidin-1- yl)cyclohexyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₅H₃₁N₇O₃FS [M + H]⁺: 528, found 528. 18-31

Cis 2-(4-(3-Fluoroazetidin-1- yl)-1-(3-((2-methyl-1,1- dioxido-2,3-dihydro- benzo[d]isothiazol-6- yl)amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₅H₂₉N₇O₃SF [M + H]⁺: 526, found 526. 18-32

Trans 2-(4-(3-Fluoroazetidin- 1-yl)-1-(3-((2-methyl-1,1- dioxido-2,3-dihydro- benzo[d]isothiazol-6- yl)amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₅H₂₉N₇O₃SF [M + H]⁺: 526, found 526. 18-33

Cis 2-(4-(Dimethylamino)-1- (3-((2-methyl-1,1-dioxido-2,3- dihydrobenzo-[d]isothiazol-6- yl)amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₃₀N₇O₃S [M + H]⁺: 496, found 496. 18-34

Trans 2-(4-(Dimethylamino)- 1-(3-((2-methyl-1,1-dioxido- 2,3-dihydrobenzo- [d]isothiazol-6-yl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₄H₃₀N₇O₃S [M + H]⁺: 496, found 496. 18-35

Trans 2-(4-(3-Fluoroazetidin- 1-yl)-1-(3-((2-methyl-1,1- dioxido-2,3-dihydro- benzo[d]isothiazol-6- yl)amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₈H₃₅N₇O₃SF [M + H]⁺: 568, found 568. 18-36

Cis 2-(4-(3-fluoroazetidin-1- yl)-1-(3-((2-methyl-1,1- dioxido-2,3-dihydro- benzo[d]isothiazol-6- yl)amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₈H₃₅N₇O₃SF [M + H]⁺: 568, found 568. 18-37

Trans 2-(1-(3-((2-(tert-butyl)- 1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)-4-(dimethylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₃₆N₇O₃S [M + H]⁺: 538, found 538. 18-38

Cis 2-(1-(3-((2-(tert-butyl)- 1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin-1- yl)-4-(dimethylamino) cyclohexyl)acetonitrile LRMS (ESI) calc'd for C₂₇H₃₆N₇O₃S [M+H]⁺: 538, found 538. 18-39

4-((1-(1-(cyanomethyl)-4- oxocyclohexyl)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-3-yl)amino)-N,N- dimethylbenzenesulfonamide LRMS (ESI) calc'd for C₂₂H₂₅N₆O₄S [M + H]⁺: 469, found 469.

Example 19-1 (2S,5S)—N-(tert-butyl)-5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxamide

Step 1: (2S,5S)-5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylic acid

To a solution of (2S,5S)-tert-butyl 5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate (Example 5-41) (390 mg, 0.654 mmol) in DCM (6.5 mL) was added TFA (0.50 mL, 6.5 mmol) portionwise at 25° C. The reaction solution was stirred overnight, diluted in DCM and quenched by the addition of saturated ammonium chloride solution. The reaction mixture was extracted with iPA/CHCl₃ (×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a solid.

Step 2: (2S,5S)—N-(tert-butyl)-5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxamide (19-1)

To (2S,5S)-5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylic acid (30 mg, 0.046 mmol) in DMF (0.4 mL), was added tert-butylamine (24 μL, 0.23 mmol), DIPEA (40 μL, 0.229 mmol) and HATU (52.4 mg, 0.138 mmol). The reaction was stirred at room temperature for 4 hours, then concentrated and purified by mass triggered reverse phase HPLC using acetonitrile in water with 0.1% TFA modifier to afford 19-1. LRMS (ESI) calc'd for C₂₉H₃₈N₇O₅S [M+H]⁺: 596. found 596. ¹H NMR (600 MHz, DMSO-d6): δ 11.32 (d, J=5.8 Hz, 1H), 8.66 (s, 1H), 7.64-7.62 (d, J=7.1 Hz, 1H), 7.56-7.54 (d, J=8.2 Hz, 1H), 7.19 (t, J=5.8 Hz, 1H), 6.90 (s, 1H), 6.73-6.72 (d, J=7.6 Hz, 1H), 4.46 (s, 1H), 4.42-4.40 (d, J=11.7 Hz, 1H), 3.88 (d, J=11.2 Hz, 2H), 3.85-3.84 (d, J=11.2 Hz, 1H), 3.48 (d, J=11.7 Hz, 2H), 2.63-2.62 (d, J=12.9 Hz, 2H), 2.97-2.94 (d, J=15.8 Hz, 2H), 1.69 (m, 2H), 1.42 (s, 9H), 1.27 (s, 9H).

The following examples outlined in Table 31 were prepared by analogy using the general procedure outlined above.

TABLE 31 Example Structure Compound Name LRMS 19-2

(2S,5S)-N-tert-butyl-5-{3- [(2-tert-butyl-1,1-dioxido- 2,3-dihydro-1,2- benzisothiazol-5- yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl}-5- (cyanomethyl)-N- methyltetrahydro-2H- pyran-2-carboxamide LRMS (ESI) calc'd for C₃₀H₄₀N₇O₅S [M + H]⁺: 610, found 610. 19-3

(2S,5S)-isopropyl 5-(3-((2- (tert-butyl)-1,1-dioxido- 2,3-dihydrobenzo [d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro- 2H-pyran-2-carboxylate LRMS (ESI) calc'd for C₂₈H₃₅N₆O₆S [M + H]⁺: 583, found 583.

Example 20-1 (S)-2-(3-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile

Step 1: (S)-4-((4-(benzyloxy)-1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-v)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-2-methylbenzoic acid

To an oven dried pressure tube equipped with magnetic sir bar under an atmosphere of nitrogen was charged with (S)-2-(3-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile (I-17B) (1.5 g, 4.1 mmol), 4-bromo-2-methylbenzoic acid (1.6 g, 7.4 mmol), potassium acetate (1.10 g, 11.4 mmol), and t-Bu XPhos 3rd Generation precatalyst (0.36 g, 0.50 mmol). The flasks was degassed by successive evacuation/nitrogen backfill (×3) and t-amyl alcohol (41.3 mL) was added. The reaction mixture was heated to 90° C. for 16 hours, then concentrated in vacuo and purified by silica chromatography, eluting with a hexanes/EtOAc gradient to yield the title compound. LRMS (ESI) calc'd for C₂₈H₂₈N₅O₄ [M+H]⁺: 498. found 498. ¹H NMR (CDCl₃, 500 MHz): δ 8.08 (d, J=8.64 Hz, 1H), 7.93 (d, J=6.5 Hz, 1H), 7.63 (s, 1H), 7.60-7.57 (m, 2H), 7.55-7.46 (m, 3H), 7.36 (d, J=8.8 Hz, 1H), 7.19-7.14 (m, 2H), 5.67 (s, 2H), 4.37 (d, J=12.0 Hz, 1H), 4.19 (d, J=12.2 Hz, 1H), 3.88 (m, 1H), 3.77 (m, 1H), 3.24 (d, J=17.1 Hz, 1H), 3.10 (d, J=17.1 Hz, 1H), 2.78 (m, 1H), 2.66 (s, 3H), 2.53 (m, 1H), 1.88-1.74 (m, 2H).

Step 2: (S)-4-((1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-2-methylbenzoic acid

To a solution of (S)-4-((4-(benzyloxy)-1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-2-methylbenzoic acid (440 mg, 0.9 mmol) in EtOAc (9 mL), was added Pd/C (188 mg, 0.2 mmol, 10 wt. %). The reaction mixture was stirred under an atmosphere of H₂ for 4 hours, diluted with EtOAc, and filtered through a pad of Celite. Concentration in vacuo afforded a residue that was purified by silica chromatography, eluting with a hexanes/EtOAc gradient to yield the title compound. LRMS (ESI) calc'd for C₂₁H₂₂N₅O₄ [M+H]⁺: 408. found 408.

Step 3: (S)-2-(3-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile (20-1)

A reaction vial with magnetic sir bar was charged with (S)-4-((1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-2-methylbenzoic acid (15 mg, 0.040 mmol), HATU (28 mg, 0.070 mmol), Hunig's base (26 μL, 0.15 mmol), DMF (0.13 mL), and 4,4-difluoropiperidine (9 mg, 0.07 mmol). The reaction mixture was stirred at room temperature for 16 hours, and then purified by reverse phase chromatography using acetonitrile in water with 0.1% TFA modifier to yield 20-1. LRMS (ESI) calc'd for C₂₆H₂₉F₂N₆O₃[M+H]⁺: 511. found 511. ¹H NMR (DMSO, 500 MHz): δ 11.29 (s, 1H), 8.28 (s, 1H), 7.54 (d, J=11.4 Hz, 2H), 7.19-7.15 (m, 2H), 6.68 (d, J=7.5 Hz, 1H), 4.32 (d, J=12.1 Hz, 1H), 3.96-3.92 (m, 4H), 3.69-3.65 (m, 2H), 3.37-3.20 (m, 4H), 2.64 (m, 1H), 2.21 (s, 3H), 2.05-2.01 (m, 4H), 1.70 (m, 1H), 1.60 (m, 1H).

Table 32 discloses Examples that were prepared in analogy to 20-1, using the appropriate starting material. In certain instances another amide coupling reagent such as HOBt and EDC could be employed in the last step.

TABLE 32 Example Structure Compound Name LRMS 20-2

2-((S)-3-(3-((3-methyl-4- ((S)-2-methylpiperidine- 1-carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran- 3-yl)acetonitrile (from I- 17B) LRMS (ESI) Calc'd for C₂₇H₃₃N₆O₃ [M + H]⁺: 489, found 489. 20-3

2-((S)-3-(3-((3-methyl-4- ((R)-2-methylpiperidine- 1-carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran- 3-yl)acetonitrile (from I- 17B) LRMS (ESI) Calc'd for C₂₇H₃₃N₆O₃ [M + H]⁺: 489, found 489. 20-4

(S)-2-(3-(3-((4-(4-hydroxy-4- methylpiperidine-1-carbonyl)- 3-methylphenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro-2H- pyran-3-yl)acetonitrile (from I- 17B) LRMS (ESI) Calc'd for C₂₇H₃₃N₆O₄ [M + H]⁺: 505, found 505. 20-5

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-(morpholine-4- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) Calc'd for C₃₀H₃₇N₆O₆ [M + H]⁺: 577, found 577. 20-6

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3-methyl- 4-(thiomorpholine-4-carbonyl) phenyl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A) LRMS (ESI) Calc'd for C₃₀H₃₇N₆O₅S [M + H]⁺: 593, found 593. 20-7

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-(pyrrolidine-1- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) Calc'd for C₃₀H₃₇N₆O₅ [M + H]⁺: 561, found 561. 20-8

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-3- methylmorpholine-4- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A. Derived from Peak 1 via SFC: Chiralcel OJ- H, 20% MeOH in CO₂, Tr = 7.1 minutes) LRMS (ESI) Calc'd for C₃₁H₃₉N₆O₆ [M + H]⁺: 591, found 591. 20-9

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-3- methylmorpholine-4- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A. Derived from Peak 2 via SFC: Chiralcel OJ- H, 20% MeOH in CO₂, Tr = 9.3 minutes) LRMS (ESI) Calc'd for C₃₃H₃₉N₆O₆ [M + H]⁺: 591, found 591. 20-10

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-2- methylmorpholine-4- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A. Derived from Peak 1 via SFC: Chiralpak AD- H, 20% iPrOH in CO₂, Tr = 10.3 minutes) LRMS (ESI) Calc'd for C₃₁H₃₉N₆O₆ [M + H]⁺: 591, found 591. 20-11

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-((S or R)-2- methylmorpholine-4- carbonyl)phenyl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A. Derived from Peak 2 via SFC: Chiralpak AD- H, 20% iPrOH in CO₂, Tr = 11.7 minutes) LRMS (ESI) Calc'd for C₃₁H₃₉N₆O₆ [M + H]⁺: 591, found 591. 20-12

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- ((2S,6S or 2R,6R)-2,6- dimethylmorpholine-4- carbonyl)-3- methylphenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A. Derived from Peak 1 via SFC: Chiralpak AD- H, 20% i-PrOH in CO₂, Tr = 9.4 minutes) LRMS (ESI) Calc'd for C₃₂H₄₁N₆O₆ [M + H]⁺: 605, found 605. 20-13

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- ((2S,6S or 2R,6R)-2,6- dimethylmorpholine-4- carbonyl)-3- methylphenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A) (Derived from Peak 2 via SFC: Chiralpak AD-H, 20% i-PtOH in CO₂, Tr = 11.0 mins) LRMS (ESI) Calc'd for C₃₂H₄₁N₆O₆ [M + H^(]+): 605, found 605. 20-14

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((4- (ethyl(2,2,2-trifluoroethyl) carbamoyl)-3-methylphenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₀H₃₆F₃N₆O₅ [M + H]⁺: 617, found 617. 20-15

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3- methyl-4-(methyl(2,2,2- trifluoroethyl)carbamoyl) phenyl)amino)-4- oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₉H₃₄F₃N₆O₅ [M + H]⁺: 603, found 603. 20-16

(2S,5S)-tert-butyl 5-(3-((4- ((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane-5- carbonyl)-3- methylphenyl)amino)-4-oxo- 4,5-dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro-2H- pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₃₁H₃₆N₆O₆ [M + H]⁺: 589, found 589.

Example 21-1 (2S,5S)-tert-butyl 5-(cyanomethyl)-5-(3-((2-methylbenzo[d]thiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate

Step 1: (2S,5S)-tert-butyl 5-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate

To a solution of (2S,5S)-tert-butyl 5-(3-amino-4-(benzyloxy)-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate (4.64 g, 10.0 mmol) in a mixture of EtOAc (66.7 mL) and MeOH (33.3 mL) at room temperature, was added palladium on carbon (1.06 g, 10 wt. %). The flask was sealed, and evacuated and backfilled with hydrogen (×3). The reaction was then stirred at room temperature for 18 hours under 1 atmosphere of hydrogen. The reaction was then diluted with MeOH, filtered through Celite, and the filter cake was washed with additional MeOH. The filtrate was concentrated in vacuo to give the title compound as a solid. LRMS (ESI) Calc'd for C₂₆H₂₉N₆O₄S [M+H]⁺: 521. found 521.

Step 2: (2S,5S)-tert-butyl 5-(cyanomethyl)-5-(3-((2-methylbenzo[d]thiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate (21-1)

(2S,5S)-tert-Butyl 5-(3-amino-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate (93 mg, 0.25 mmol), 6-bromo-2-methylbenzo[d]thiazole (62.7 mg, 0.275 mmol), Pd₂(dba)₃ (27.5 mg, 0.030 mmol), t-Bu-X-Phos (26 mg, 0.060 mmol) and potassium acetate (49.1 mg, 0.500 mmol) were added to a 5 mL Biotage microwave vial followed by 2-propanol (2.50 mL). The vial was sealed and degassed by evacuation/argon backfill (×3) and heated to 85° C. for 18 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken into DMSO (2.50 mL), filtered, and the resulting solution was purified directly by mass directed reverse-phase HPLC (5-50% acetonitrile in water with 0.1% TFA modifier). Fractions containing pure product were frozen and lyophilized to afford the title compound as the TFA salt and as a solid. LRMS (ESI) Calc'd for C₁₈H₂₄N₅O₄ [M+H]⁺: 374. found 374. ¹H NMR (DMSO-d₆, 500 MHz): δ 8.44 (d, J=2.3 Hz, 1H), 8.38 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (dd, J=8.5, 2.5 Hz, 1H), 7.20 (dd, J=7.5, 6.0 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 4.35 (d, J=11.7 Hz, 1H), 4.22 (dd, J=9.4, 4.2 Hz, 1H), 4.12 (d, J=12.2 Hz, 1H), 3.43 (AB, J=17.4 Hz, 1H), 3.38 (AB, J=17.4 Hz, 1H), 2.74 (s, 3H), 2.56 (m, 1H), 2.44 (m, 1H), 1.92 (m, 2H), 1.46 (s, 9H).

The following examples outlined in Table 32 were prepared by analogy using the general procedure outlined above for Example 21-1. In select cases, the general procedure could alternatively be modified to utilize K₃PO₄ base, [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (t-BuXPhos Pd G3) precatalyst in place of the individual phosphine and palladium source, and/or t-amyl alcohol. Additionally, in certain instances the cross coupling could be run between 70-90° C.

TABLE 32 Example Structure Compound Name LRMS 21-2

[(1R,2R)-1-{3-[(3,3- dimethyl-2-oxo-2,3- dihydro-1H-indol-6- yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl}-2- fluorocyclohexyl] acetonitrile (from I-19A) LRMS (ESI) calc'd for C₂₄H₂₆N₆O₂F [M + H]⁺: 449, found 449. 21-3

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((3,3- dimethyl-2-oxoindolin-6- yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)tetrahydro- 2H-pyran-2-carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₈H₃₃N₆O₅ [M + H]⁺: 533, found 533. 21-4

[(3S)-3-{3-[(3,3-dimethyl-2- oxo-2,3-dihydro-1H-indol- 6-yl)amino]-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl}tetrahydro- 2H-pyran-3-yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₃H₂₅N₆O₃ [M + H]⁺: 433, found 433. 21-5

[(3S)-3-{3-[(2-methyl-1,3- benzothiazol-6-yl)amino]- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl}tetrahydro-2H-pyran-3- yl]acetonitrile (from I-17B) LRMS (ESI) calc'd for C₂₁H₂₁N₆O₂S [M + H]⁺: 421, found 421. 21-6

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(3-((2- fluoropyridin-4-yl)amino)- 4-oxo-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A) LRMS (ESI) calc'd for C₂₃H₂₆FN₆O₄ [M + H]⁺: Calc'd 469, found 469. 21-7

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((R or S)-2,2,2- trifluoro-1-methoxyethyl) phenyl)amino)-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. The mixture of diastereomers was purified as the free pyridone by chiral SFC using AD-H column and 15% MeOH with 0.25% DMEA,Tr = 5.6 minutes) LRMS (ESI) calc'd for C₂₇H₃₁F₃N₅O₅ [M + H]⁺: Calc'd 562, found 562. 21-8

(2S,5S)-tert-butyl 5- (cyanomethyl)-5-(4-oxo-3- ((4-((S or R)-2,2,2- trifluoro-1-methoxyethyl) phenyl)amino)-4,5- dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl)tetrahydro-2H-pyran-2- carboxylate (from I-14-1A. The mixture of diastereomers was purified as the free pyridone by chiral SFC using AD-H column and 15% MeOH with 0.25% DMEA, Tr = 7.5 minutes) LRMS (ESI) calc'd for C₂₇H₃₁F₃N₅O₅ [M + H]⁺: Calc'd 562, found 562. 21-9

tert-butyl 4-(cyanomethyl)- 4-[4-oxo-3-({4-[(1R or 1S)- 2,2,2-trifluoro-1- methoxyethyl]phenyl} amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]piperidine-1-carboxylate The mixture of diastereomers was purified as the free pyridone by chiral SFC using AD-H column and 20% MeOH with 0.25% DMEA, Tr = 3.7 minutes. LRMS (ESI) calc'd for C₂₇H₃₂F₃N₆O₄ [M + H]⁺: Calc'd 561, found 561. 21-10

tert-butyl 4-(cyanomethyl)- 4-[4-oxo-3-({4-[(1S or 1R)- 2,2,2-trifluoro-1- methoxyethyl]phenyl} amino)-4,5-dihydro-1H- pyrazolo[4,3-c]pyridin-1- yl]piperidine-1-carboxylate The mixture of diastereomers was purified as the free pyridone by chiral SFC using AD-H column and 20% MeOH with 0.25% DMEA, Tr = 5.3 minutes. LRMS (ESI) calc'd for C₂₇H₃₂F₃N₆O₄ [M + H]⁺: Calc'd 561, found 561. 21-11

tert-butyl 4-(cyanomethyl)- 4-(3-((4-(4,4- difluoropiperidine-1- carbonyl)-3-methylphenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₃₁H₃₈F₂N₇O₄ [M + H]⁺: 610, found 610. 21-12

tert-butyl-4-(3-((4-(8-oxa-3- azabicyclo[3.2.1]octane-3- carbonyl)-3-methylphenyl) amino)-4-oxo-4,5-dihydro- 1H-pyrazolo[4,3-c]pyridin- 1-yl)-4- (cyanomethyl)piperidine-1- carboxylate LRMS (ESI) calc'd for C₃₂H₄₀N₇O₅ [M + H]⁺: 602, found 602. 21-13

tert-butyl 4-(cyanomethyl)- 4-{3-[(5-methyl-4-{3-oxa- 8-azabicyclo[3.2.1]octan-8- ylcarbonyl}cyclohexa- 1,3,5-trien-1-yl)amino]-4- oxo-5H-pyrazolo[4,3- c]pyridin-1-yl}piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₂H₄₀N₇O₅ [M + H]⁺: 602, found 602. 21-14

tert-butyl-4-(cyanomethyl)- 4-(3-(3-methyl-4- (thiomorpholine-4- carbonyl)phenylamino)-4- oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₀H₃₈N₇O₄S [M + H]⁺: 592, found 592. 21-15

tert-butyl-4-(cyanomethyl)- 4-(3-((1,1-dioxido-2-(1- (2,2,2-trifluoroethyl) piperidin-4-yl)-2,3- dihydrobenzo[d]isothiazol- 5-yl)amino)-4-oxo-4,5- dihydro-1H-pyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₂H₄₀F₃N₈O₅S [M + H]⁺: 705, found 705. 21-16

(S or R)-tert-butyl 4- (cyanomethyl)-4-(4-oxo- 3-(4-(2- (trifluoromethyl)piperidin- 2-yl)phenylamino)-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate (from I-54B) LRMS (ESI) calc'd for C₃₀H₃₇F₃N₇O₃ [M + H]⁺: 600, found 600. 21-17

(R or S)-tert-butyl 4- (cyanomethyl)-4-(4- oxo-3-(4-(2- (trifluoromethyl)piperidin- 2-yl)phenylamino)-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate (from I-54A) LRMS (ESI) calc'd for C₃₀H₃₇F₃N₇O₃ [M + H]⁺: 600, found 600. 21-18

(R or S)-tert-butyl 4- (cyanomethyl)-4-(4- oxo-3-(4-(2- (trifluoromethyl)pyrrolidin- 2-yl)phenylamino)-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate (from I-55A) LRMS (ESI) calc'd for C₂₉H₃₅F₃N₇O₃ [M + H]⁺: 586, found 586. 21-19

(S or R)-tert-butyl 4- (cyanomethyl)-4-(4- oxo-3-(4-(2- (trifluoromethyl)pyrrolidin- 2-yl)phenylamino)-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate (from I-55B) LRMS (ESI) calc'd for C₂₉H₃₅F₃N₇O₃ [M + H]⁺: 586, found 586. 21-20

tert-butyl 4-(cyanomethyl)- 4-(3-(3-methyl-4- (morpholine-4- carbonyl)phenylamino)-4- oxo-4,5- dihydropyrazolo[4,3- c]pyridin-1-yl)piperidine- 1-carboxylate LRMS (ESI) calc'd for C₃₀H₃₈N₇O₅ [M + H]⁺: 576, found 576.

Example 22 (2S,5S)-5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N-(methylsulfonyl)tetrahydro-2H-pyran-2-carboxamide

To a solution of 1,1′-carbonyldiimidazole (76 mg, 0.467 mmol) in THF (0.80 mL), was added a solution of (2S,5S)-5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylic acid (Intermediate 20) (100 mg, 0.234 mmol) in THF (0.80 mL). The reaction was stirred at reflux for 30 minutes, cooled, and then methanesulfonamide (44.5 mg, 0.467 mmol) was added followed by a solution of DBU (0.070 mL, 0.467 mmol) in THF (0.80 mL). The reaction was stirred at room temperature for two hours and then concentrated in vacuo. The crude material was dissolved in DMSO (3.0 mL), filtered, and submitted for mass-triggered HPLC purification. Lyophilization of the desired fractions gave the desired title compound as the TFA salt. LRMS (ESI) calc'd for C₂₁H₂₂ClN₆O₅S [M+H]⁺: 505. found: 505. ¹H NMR (500 MHz, DMSO-d6): δ 11.76 (s, 1H), 11.37 (d, J=6.2 Hz, 1H), 8.34 (s, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.34 (d, J=9.0 Hz, 2H), 7.25 (dd, J=7.4, 6.0 Hz, 1H), 6.77 (d, J=7.4 Hz, 1H), 4.42 (d, J=12.5 Hz, 1H), 4.25 (dd, J=13.8, 3.3 Hz, 1H), 4.12 (d, J=11.3 Hz, 1H), 3.60 (AB, J=11.3 Hz, 1H), 3.55 (AB, J=11.3 Hz, 1H), 3.34 (s, 3H), 2.65 (m, 1H), 2.43 (m, 2H), 2.00 (m, 1H), 1.89 (m, 1H).

Example 23 (2S,5S)-5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N,N-dimethyltetrahydro-2H-pyran-2-carboxamide

(2S,5S)-5-(3-((4-Chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylic acid (Intermediate 20) (30 mg, 0.070 mmol) and HATU (53.3 mg, 0.140 mmol) were dissolved in DMF (0.5 mL) and stirred at room temperature for 5 minutes. Dimethylamine (0.070 mL, 0.140 mmol, 2M in THF) and DIPEA (0.037 mL, 0.21 mmol) were then added and the reaction was stirred at room temperature for 1 hour. The solution was diluted with DMSO (0.5 mL) and submitted for mass-triggered reverse phase purification. The desired fractions were reduced in vacuo to give the title compound. LRMS (ESI) calc'd for C₂₂H₂₄ClN₆O₃[M+H]⁺: 455. found: 455. ¹H NMR (500 MHz, DMSO-d6): δ 11.36 (d, J=6.0 Hz, 1H), 8.34 (s, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.25 (dd, J=5.9, 7.6 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 4.51 (dd, J=10.4, 3.6 Hz, 1H), 4.35 (d, J=11.6 Hz, 1H), 4.17 (d, J=11.6 Hz, 1H), 3.41 (s, 2H), 3.08 (s, 3H), 2.89 (s, 3H), 2.66 (m, 1H), 2.49 (m, 1H), 1.97 (m, 1H), 1.82 (m, 1H).

Example 24 2-((3S,6S)-3-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)acetonitrile

Step 1: (2S,5S)-5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide

(2S,5S)-5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylic acid (Intermediate 20) (840 mg, 1.96 mmol) and HATU (1.49 g, 3.93 mmol) were dissolved in DMF (4.0 mL) and stirred at room temperature for 5 minutes before a solution of N, O-dimethylhydroxylamine hydrochloride (383 mg, 3.93 mmol) and DIPEA (1.03 mL, 5.89 mmol) in DMF (2.0 mL) was added. The reaction was stirred at room temperature for 1 hour, then diluted with ethyl acetate and washed with water, brine, and dried over MgSO₄. The solvent was filtered, and concentrated in vacuo and then purified by silica chromatography, eluting with a 0-5% methanol in dichloromethane gradient to afford the title compound. LRMS (ESI) calc'd for C₂₂H₂₄ClN₆O₄[M+H]⁺: 471. found: 471.

Step 2: 2-((3S,6S)-6-acetyl-3-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile

(2S,5S)-5-(3-((4-Chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N-methoxy-N-methyltetrahydro-2H-pyran-2-carboxamide (100 mg, 0.212 mmol) was dissolved in THF (2.0 mL) and the flask was then sealed, flushed with argon, and cooled to −78° C. Methylmagnesium bromide (0.283 mL, 0.849 mmol, 3M in diethyl ether) was then added. The reaction was stirred for 2 hours to 0° C., and then stirred for an additional hour before being quenched with water. The reaction was then extracted with ethyl acetate (×3) and the combined organic layers was dried using MgSO₄, filtered, concentrated in vacuo. The crude material was purified by silica chromatography, eluting with a 0-10% methanol in dichloromethane gradient to afford the title compound. LRMS (ESI) calc'd for C₂₁H₂₁ClN₅O₃[M+H]⁺: 426. found: 426.

Step 3: 2-((3S,6S)-3-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)acetonitrile (Example 24)

A solution of 2-((3S,6S)-6-acetyl-3-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile (26 mg, 0.061 mmol) in THF (2.0 mL) was sealed, flushed with argon, and cooled to −78° C. Methylmagnesium bromide (0.081 mL, 0.244 mmol, 3M in diethyl ether) was then added and the reaction was stirred for 2 hours before being quenched with saturated aqueous NH₄Cl. The reaction was then extracted using ethyl acetate (×3), and the combined organic layers were washed with brine, dried with MgSO₄, filtered and concentrated in vacuo. The crude material was purified using mass-triggered reverse phase HPLC. The fractions were pooled and concentrated in vacuo to give Example 24. LRMS (ESI) calc'd for C₂₂H₂₅ClN₅O₃[M+H]⁺: 442. found: 442 ¹H NMR (500 MHz, Acetone-d6): δ 10.27 (d, J=4.2 Hz, 1H), 8.29 (s, 1H), 7.78 (d, J=8.9 Hz, 2H), 7.36 (d, J=8.9 Hz, 2H), 7.32 (d, J=7.1 Hz, 1H), 6.81 (d, J=7.1 Hz, 1H), 4.61 (d, J=11.0, 2.8 Hz, 1H), 3.99 (d, J=11.0 Hz, 1H), 3.49 (s, 2H), 3.41 (d, J=11.1 Hz, 1H), 2.93 (m, 1H), 2.51 (m, 1H), 2.03 (m, 1H), 1.86 (m, 1H), 1.26 (3H), 1.24 (s, 3H).

Biological Assays Jak Biochemical HTRF Assay Protocol

The ability of compounds to inhibit the activity of JAK1, JAK2, JAK3, and Tyk2 was measured using a recombinant purified GST-tagged catalytic domain for each enzyme (Invitrogen JAK1 #M4290, JAK2 #M4290, JAK3 #M4290, Tyk2 #M4290) in an HTRF format biochemical assay. The reactions employed a common peptide substrate, LCB-EQEDEPEGDYFEWLW-NH2 (in-house). The basic assay protocol is as follows: First, 250 nL of diluted compounds in DMSO were dispensed into the wells of a dry 384-well Black plate (Greiner #781076) using a Labcyte Echo 555 acoustic dispenser. Subsequent reagent additions employed an Agilent Bravo. Next, 18 μL of 1.11× enzyme and 1.11× substrate in 1× assay buffer (Invitrogen kinase buffer #PV3189, 2 mM DTT, 0.05% BSA) were added to the wells and shaken and then preincubated for 30 minutes at room temperature to allow compound binding to equilibrate. After equilibration, 2 μL of 10×ATP in 1× assay buffer was added to initiate the kinase reaction and the plates were shaken and then incubated at room temperature for 120 minutes. At the end of the incubation, 20 μL of 2× stop buffer (streptavidin-Dylight 650 (Thermo #84547B/100 mL), Eu-tagged pY20 antibody (Perkin Elmer #AD0067), EDTA, HEPES, and Triton) was added to quench the reaction. Plates were shaken and centrifuged and then incubated 60 minutes at room temperature and then read on a Perkin Elmer Envision (λex=337 nm, λem=665 and 615 nm, TRF delay time=20 μs). HTRF signal=10,000*665 nm reading/615 nm reading. After normalization to untreated controls, the percent inhibition of the HTRF signal at each compound concentration was calculated. The plot of percent inhibition versus the log of compound concentration was fit with a 4-parameter dose response equation to calculate IC₅₀ values.

Final reaction conditions were:

[E] [S] [ATP] [Eu-pY20] [SA-Dylight] Enzyme (nM) (μM) (μM) (nM) (nM) JAK1 1.405 0.75 31.8 9 312.5 JAK2 0.052 0.75 8.5 9 312.5 JAK3 0.031 0.75 2.9 9 312.5 Tyk2 2.612 0.75 6.9 9 312.5

Compound concentrations tested were 1496, 499, 175, 49.9, 18.7, 6.2, 2.1, 0.75, 0.24, 0.075, and 0.0125 nM, with 1.25% residual DMSO.

Biological Data

Examples of the instant invention were evaluated in JAK1 and JAK2 in vitro binding assays as described above. The following table tabulates the JAK1 IC₅₀ values and JAK2 IC₅₀ values disclosed for the instant invention.

Example JAK1 IC₅₀ (nM) JAK2 IC₅₀ (nM)  1-1 2.23 24.97  1-2 0.45 11.86  2-1 48.2 60.3  2-2 49.91 39.82  2-3 67.56 >1496  2-4 207.9 >1481  2-5 20.26 490  3 40.76 2.51  4-1 32.90 217.90  4-2 2.47 37.72  4-3 2.64 35.95  5-1 0.22 0.28  5-2 0.21 0.44  5-3 0.43 1.11  5-4 0.12 0.23  5-5 0.28 0.31  5-6 0.11 0.19  5-7 8.23 46.98  5-8 1.96 20.03  5-9 0.10 0.07  5-10 0.23 1.09  5-11 0.20 0.17  5-12 0.12 0.61  5-13 0.50 4.86  5-14 1.07 17.68  5-15 0.27 3.45  5-16 0.12 0.35  5-17 0.09 0.08  5-18 0.10 0.12  5-19 0.08 0.08  5-20 0.15 0.12  5-21 0.15 0.14  5-22 0.15 0.19  5-23 0.24 0.34  5-24 0.20 0.25  5-25 0.19 0.30  5-26 0.09 0.10  5-27 0.22 2.81  5-28 0.13 0.29  5-29 13.46 27.69  5-30 12.63 58.01  5-31 0.26 1.64  5-32 0.13 0.87  5-33 0.03 0.23  5-34 4.74 22.56  5-35 3.43 29.31  5-36 0.09 0.34  5-37 1.93 17.08  5-38 0.23 0.49  5-39 0.06 0.43  5-40 2.06 14.58  5-41 0.09 0.11  5-42 1.60 7.21  5-43 0.07 0.14  5-44 0.14 0.37  5-45 0.82 8.55  5-46 3.53 43.53  5-47 7.27 108.00  5-48 0.22 2.26  5-49 0.20 0.34  5-50 11.83 34.51  5-51 0.18 0.49  5-52 11.74 30.31  5-53 0.19 0.57  5-54 0.12 1.62  5-55 0.05 0.12  5-56 0.12 0.19  5-57 0.08 0.13  5-58 0.14 0.18  5-59 0.10 0.15  5-60 1.07 0.46  5-61 0.64 12.68  5-62 0.31 0.32  5-63 2.10 0.70  5-64 0.57 0.46  5-65 0.21 3.22  5-66 0.26 0.43  5-67 0.47 0.52  5-68 0.25 0.33  5-69 0.12 0.17  5-70 0.07 0.58  5-71 0.08 0.15  5-72 0.06 0.26  5-73 0.12 0.35  5-74 0.06 0.27  5-75 0.12 0.37  5-76 0.90 7.89  5-77 0.16 0.34  5-78 0.18 2.12  5-79 0.78 1.27  5-80 0.08 1.21  5-81 0.24 3.73  5-82 0.10 0.31  5-83 1.97 21.6  5-84 <0.02 0.05  5-85 0.07 0.17  5-86 0.07 0.11  5-87 0.04 0.05  5-88 0.46 1.56  5-89 0.50 1.74  5-90 0.33 0.41  5-91 0.14 0.23  5-92 0.09 0.13  5-93 0.14 0.37  5-94 0.04 0.18  5-95 0.07 0.20  5-96 0.07 0.34  5-97 0.09 0.14  5-98 0.07 0.18  5-99 0.05 0.14  5-100 0.14 0.26  5-101 0.18 0.40  5-102 0.10 0.20  5-103 0.07 0.23  5-104 0.07 0.27  5-105 0.23 0.55  5-106 0.39 0.99  5-107 0.20 0.33  5-108 0.12 0.23  5-109 0.25 0.29  5-110 0.16 0.59  5-111 0.09 0.35  5-112 1.07 2.53  5-113 0.28 0.34  5-114 0.33 1.31  5-115 0.33 0.99  5-116 0.61 1.22  5-117 0.45 1.36  5-118 0.34 0.76  5-119 0.15 0.63  5-120 0.07 0.12  5-121 0.04 0.51  5-122 0.22 0.48  5-123 0.23 0.46  5-124 0.58 3.69  5-125 0.27 2.71  5-126 4.53 37.3  5-127 4.76 30.5  5-128 0.22 2.24  5-129 2.07 3.54  5-130 0.50 1.07  5-131 0.25 0.98  5-132 0.39 0.68  5-133 0.44 1.38  5-134 0.70 1.07  5-135 0.98 1.53  5-136 0.56 1.01  5-137 1.90 5.85  5-138 0.31 1.51  5-139 0.76 1.44  5-140 0.32 0.74  5-141 0.18 0.43  5-142 0.13 0.33  5-143 0.18 0.66  5-144 0.10 0.21  5-145 0.19 1.22  5-146 0.30 2.00  5-147 0.32 2.95  5-148 0.08 0.84  5-149 0.12 0.23  5-150 0.10 0.14  5-151 0.09 0.10  5-152 0.09 0.68  5-153 0.09 0.08  5-154 0.09 0.08  5-155 0.18 0.39  5-156 0.17 0.30  5-157 0.19 0.27  5-158 0.28 0.38  5-159 0.24 0.30  5-160 0.22 0.58  5-161 0.29 0.51  5-162 2.76 12.88  5-163 1.96 2.21  5-164 0.59 0.68  5-165 0.46 1.00  5-166 1.28 1.95  5-167 0.83 4.32  5-168 0.12 0.51  5-169 0.10 0.41  5-170 0.14 0.48  5-171 0.07 0.18  5-172 0.75 1.14  5-173 0.07 0.07  5-174 0.06 0.06  5-175 0.09 0.06  5-176 0.05 0.09  5-177 0.09 0.16  5-178 0.04 0.17  5-179 0.08 0.26  5-180 0.84 1.84  5-181 0.29 0.95  5-182 0.25 0.57  5-183 0.17 0.47  5-184 0.20 0.60  5-185 0.08 1.50  5-186 0.36 1.34  5-187 0.19 0.58  5-188 0.11 0.34  5-189 0.14 0.17  5-190 0.21 0.38  5-191 0.16 0.52  5-192 0.17 0.30  5-193 0.42 0.66  5-194 0.52 0.82  5-195 0.56 0.68  5-196 0.15 0.33  5-197 0.13 1.13  5-198 0.16 0.39  5-199 0.15 0.33  5-200 1.15 0.53  5-201 0.49 0.27  5-202 0.39 1.20  5-203 0.15 0.27  5-204 0.29 0.48  5-205 0.17 0.20  5-206 0.13 0.16  5-207 0.19 0.26  5-208 0.24 0.31  5-209 0.32 0.35  5-210 0.41 0.51  5-211 0.19 0.12  5-212 0.22 0.15  5-213 0.19 0.29  5-214 0.20 0.32  5-215 0.07 0.63  5-216 0.14 1.16  5-217 0.07 0.77  5-218 0.16 0.73  5-219 0.13 1.36  5-220 0.14 0.19  5-221 0.35 5.29  5-222 0.13 0.64  5-223 0.07 0.82  5-224 0.36 3.00  5-225 0.15 2.30  5-226 0.11 2.94  5-227 0.15 0.76  5-228 0.25 1.06  5-229 0.34 1.39  5-230 0.12 0.16  5-231 0.12 0.21  5-232 0.27 0.60  5-233 0.36 0.40  5-234 0.63 0.99  5-235 0.14 0.21  5-236 0.12 0.25  5-237 0.15 0.28  5-238 0.11 0.48  5-239 2.29 16.7  5-240 13.0 79.9  5-241 2.62 23.4  5-242 14.0 129.6  5-243 6.62 100.4  5-244 23.0 347.8  5-245 3.93 42.3  5-246 16.8 172.5  5-247 0.11 2.24  5-248 0.39 9.56  5-249 1.13 2.43  5-250 4.34 12.12  5-251 0.06 0.78  5-252 0.34 0.84  5-253 0.72 1.40  5-254 0.66 1.40  5-255 0.14 3.32  5-256 0.04 0.06  5-257 2.08 3.17  5-258 0.07 0.08  5-259 0.04 0.05  5-260 0.26 2.35  5-261 2.26 2.74  5-262 0.09 0.08  5-263 0.48 0.77  5-264 0.51 0.79  5-265 0.05 0.04  5-266 0.05 0.04  5-267 2.42 4.02  5-268 2.63 4.78  5-269 0.11 0.09  5-270 0.12 0.13  5-271 0.25 3.27  5-272 0.06 0.10  5-273 0.17 0.14  5-274 0.36 0.26  5-275 0.17 0.09  5-276 0.57 0.40  5-277 0.05 0.05  5-278 0.20 2.65  5-279 0.18 0.12  5-280 7.33 9.56  5-281 7.90 10.04  5-282 0.33 0.49  5-283 0.33 0.43  5-284 0.15 0.24  5-285 0.15 0.21  5-286 0.24 0.33  5-287 0.25 0.35  5-288 0.15 0.30  5-289 0.88 1.89  5-290 0.25 0.48  5-291 0.15 0.34  5-292 1.20 1.92  5-293 0.43 0.68  5-294 0.22 0.37  5-295 0.42 0.60  5-296 0.65 0.91  6 421.30 >1496  7 0.09 1.90  8-1 0.17 0.38  8-2 0.44 1.16  8-3 2.32 8.62  8-4 6.90 33.07  8-5 0.20 0.54  8-6 1.94 12.45  8-7 0.21 0.63  8-8 0.29 0.52  8-9 0.19 0.28  8-10 0.19 0.29  8-11 0.24 0.28  8-12 0.26 0.99  8-13 0.31 0.75  8-14 0.73 2.84  8-15 0.53 2.84  8-16 1.54 8.34  8-17 1.40 3.26  8-18 3.16 13.96  8-19 1.19 1.98  9-1 0.11 0.48  9-2 0.08 0.31  9-3 0.24 1.63  9-4 0.65 5.17  9-5 0.55 3.05  9-6 0.08 0.29  9-7 0.09 0.51  9-8 0.16 1.21  9-9 3.96 38.78  9-10 0.17 1.07  9-11 0.14 1.15  9-12 1.69 16.75  9-13 1.08 11.97  9-14 0.23 1.96  9-15 0.81 8.38  9-16 1.05 6.75  9-17 0.15 0.70  9-18 0.14 0.39  9-19 0.26 3.14  9-20 0.31 2.48  9-21 0.08 0.33  9-22 0.09 0.21  9-23 0.14 1.32  9-24 0.14 0.36  9-25 0.10 0.16 10-1 0.13 0.26 10-2 0.19 0.86 10-3 0.27 0.97 10-4 0.45 3.08 10-5 0.12 0.29 10-6 0.12 0.27 11-1 0.27 1.01 11-2 0.38 1.69 11-3 0.31 1.09 11-4 0.27 1.45 11-5 0.27 0.61 11-6 0.12 0.47 11-7 0.18 1.35 11-8 0.18 0.29 11-9 0.41 1.37 11-10 0.06 0.10 11-11 0.16 0.91 12 0.11 0.24 13-1 0.22 3.82 13-2 0.64 5.54 14-1 0.09 0.18 14-2 0.06 0.12 15-1 0.16 0.37 15-2 0.04 0.04 15-3 0.25 0.26 15-4 0.20 0.55 15-5 0.15 0.17 15-6 0.10 0.09 15-7 0.17 1.02 15-8 0.09 0.41 16-1 2.77 3.06 16-2 1.14 4.81 16-3 1.15 3.82 16-4 2.01 2.01 17 0.10 0.24 18-1 0.26 0.94 18-2 6.80 64 18-3 41.14 1292 18-4 6.33 101.90 18-5 4.14 84.56 18-6 0.09 1.75 18-7 2.98 19.82 18-8 0.03 2.53 18-9 1.14 102.10 18-10 73.97 1020 18-11 0.22 2.20 18-12 5.41 38.48 18-13 64.96 >1496 18-14 1.71 32.35 18-15 151.20 1137 18-16 0.15 1.43 18-17 119.90 1099 18-18 7.27 54.70 18-19 0.37 36.64 18-20 52.18 >1496 18-21 0.12 64.17 18-22 20.51 >1496 18-23 124.8 >1496 18-24 0.09 5.87 18-25 70.15 >1496 18-26 2.48 54.73 18-27 2.23 9.07 18-28 0.05 0.11 18-29 0.10 0.13 18-30 2.62 3.54 18-31 1.81 16.95 18-32 0.04 0.09 18-33 48.51 591.8 18-34 1.07 12.09 18-35 0.21 0.21 18-36 0.83 6.85 18-37 0.23 4.43 18-38 16.14 211.1 18-39 1.37 1.78 19-1 0.08 1.94 19-2 0.10 2.07 19-3 0.04 0.06 20-1 0.30 0.71 20-2 0.43 0.62 20-3 0.65 0.83 20-4 0.35 0.88 20-5 0.13 0.19 20-6 0.13 0.17 20-7 0.09 0.36 20-8 0.15 0.16 20-9 0.14 0.17 20-10 0.21 0.31 20-11 0.23 0.35 20-12 0.25 0.45 20-13 0.22 0.26 20-14 0.28 0.51 20-15 0.19 0.51 20-16 0.10 0.15 21-1 0.08 0.73 21-2 0.04 0.04 21-3 0.07 0.12 21-4 0.09 0.19 21-5 0.09 1.32 21-6 0.12 2.25 21-7 0.41 0.90 21-8 0.38 1.03 21-9 1.11 1.96 21-10 0.97 1.95 21-11 0.43 0.38 21-12 0.26 0.18 21-13 0.27 0.20 21-14 0.33 0.32 21-15 0.77 0.65 21-16 0.71 0.64 21-17 0.63 0.58 21-18 0.55 0.50 21-19 0.45 0.50 21-20 0.18 0.17 22 3.78 23.3 23 0.23 2.50 24 0.34 1.13 

1. A compound of Formula I or a pharmaceutically acceptable salt, or a stereoisimer thereof:

A is selected from aryl, heteroaryl, cycloalkylC₍₀₋₁₀₎alkyl, C₁₋₆alkyl; R² and R³ are each independently selected from hydrogen, C₁₋₄alkyl and hydroxy, wherein R² and R³ may optionally, join together with the carbon they are attached to form a 3 to 6 membered ring; X₁ is C; X₂, X₃, and X₄ are each independently selected from O, N, S, and C and provided that the formed ring system contains 0, 1, 2, or 3 atoms selected from O, N and S; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, or 4; R⁴ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, C₁₋₁₀ alkylamino(carbonyl)₀₋₁C₀₋₁₀alkyl, (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ amino C₀₋₁₀ alkyl, (C₁₋₁₀)heteroalkylamino(carbonyl)₀₋₁ C₀₋₁₀alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl, heteroarylC₀₋₁₀ alkylsulfonyl, arylC₀₋₁₀ alkylsulfonyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, C₀₋₁₀ alkylsulfamoyl, C₁₋₁₀ heteroalkylsulfamoyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl, heteroarylC₀₋₁₀ alkylsulfamoyl, arylC₀₋₁₀ alkylsulfamoyl, C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonimidoylC₀₋₁₀ alkyl, heteroarylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, arylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₁₋₂amino, —CO₂(C₀₋₁₀ alkyl), —(C₀₋₁₀ alkyl)CO₂H, —SO₂CF₃, —SO₂CF₂H, —SO₂CH₂CF₃, C₁₋₁₀ alkylsulfinyl, C₁₋₄acylaminoC₀₋₁₀ alkyl, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl, wherein two R⁴ together with the ring atom to which each is attached optionally may form a saturated ring; R⁵ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, C₀₋₁₀ alkylaminocarbonylC₀₋₁ alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, (C₁₋₁₀)heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₁₋₂ amino, —SF₅, C₀₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfonyl, heteroarylC₀₋₁₀ alkylsulfonyl, arylC₀₋₁₀ alkylsulfonyl, C₀₋₁₀ alkylsulfamoyl, C₁₋₁₀ heteroalkylsulfamoyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl, heteroarylC₀₋₁₀ alkylsulfamoyl, C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonimidoylC₀₋₁₀ alkyl, heteroarylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, arylC₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, arylC₀₋₁₀ alkylsulfamoyl, (C₀₋₁₀ alkyl)₁₋₂ amino, —CO₂(C₀₋₁₀ alkyl), —(C₀₋₁₀ alkyl)CO₂H, —SO₂CF₃, —SO₂CF₂H, —SO₂CH₂CF₃, C₁₋₁₀ alkylsulfinyl, C₁₋₄acylaminoC₀₋₁₀ alkyl, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; and wherein R⁴ and R⁵ are each optionally substituted with 1, 2, 3, or 4 R⁶ substituents and R⁶ is independently selected from: halogen, C₁₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ alkyl(carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, C₂₋₁₀ alkenyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl (carbonyl)₀₋₁oxyC₀₋₁₀ alkyl, (C₃₋₁₂)cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl, heteroarylC₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁ oxyC₀₋₁₀ alkyl, ((C₀₋₁₀)alkyl)₁₋₂aminocarbonyloxy, aryl (C₀₋₁₀)alkylaminocarbonyloxy, —CO₂(C₀₋₁₀ alkyl), —(C₀₋₁₀ alkyl)CO₂H, oxo (═O), C₀₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₁₂) cycloalkylsulfonyl, (C₃₋₁₂) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂CF₃, —SO₂CF₂H, C₁₋₁₀ alkylsulfinyl, amino, (C₁₋₁₀ alkyl)₁₋₂amino, -(oxy)₀₋₁ (carbonyl)₀₋₁N(C₀₋₁₀ alkyl)₁₋₂ C₁₋₄acylaminoC₀₋₁₀ alkyl, hydroxy, (C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)cyano, cyano, and C₁₋₆haloalkyl; and R⁶ is optionally substituted with 1, 2, or 3 R⁷ substituents selected from hydrogen, hydroxy, (C₁₋₆)alkyl, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)OH, halogen, CO₂H, —(C₀₋₆)alkylCN, —O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C₀₋₆)alkyl, C₁₋₁₀ alkylsulfonyl, oxo (O═), aminosulfonyl, —SO₂C₁₋₆alkyl, —SO₂CF₃, —SO₂CF₂H, —C₁₋₁₀ alkylsulfinyl, —O₍₀₋₁₎(C₁₋₁₀)halo, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, alkyl, amino(C₁₋₆alkyl)₀₋₂ and NH₂.
 2. A compound according to claim 1, wherein R⁵ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁ C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ C₀₋₁₀ alkyl, C₀₋₁₀ alkylaminocarbonylC₀₋₁₀alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, —SF₅, C₀₋₁₀ alkylsulfonyl, C₁₋₁₀ heteroalkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl, C₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloalkylC₀₋₁₀ alkylsulfamoyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀ alkylsulfamoyl, heteroarylC₀₋₁₀ alkylsulfamoyl, C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, arylC₀₋₁₀ alkylsulfamoyl, (C₁₋₁₀ alkyl)₁₋₂amino, —SO₂CF₃, —SO₂CF₂H, —SO₂CH₂CF₃, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl; wherein R⁵ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents.
 3. A compound according to claim 2, wherein R⁴ is selected from: halogen, oxo (═O), C₁₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl,C₁₋₁₀ heteroalkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl(oxy)₀₋₁(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀ alkyl, C₁₋₁₀ alkylamino(carbonyl)₀₋₁ C₀₋₁₀alkyl, (C₁₋₁₀)heteroalkyl(oxy)₀₋₁ (carbonyl)₀₋₁ aminoC₀₋₁₀alkyl, (C₁₋₁₀)heteroalkylamino(carbonyl)₀₋₁C₀₋₁₀alkyl, C₃₋₁₂ cycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, aryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, heteroaryl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, (C₃₋₁₂)heterocycloalkyl C₀₋₁₀ alkylaminoC₀₋₁₀ alkyl, C₀₋₁₀ alkylsulfonyl, (C₃₋₁₂)cycloalkylC₀₋₁₀alkylsulfonyl, (C₃₋₁₂)cycloheteroalkylC₀₋₁₀alkylsulfonyl, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)₂, C₀₋₁₀ alkylsulfonimidoylC₀₋₁₀ alkyl, C₁₋₁₀ heteroalkylsulfonimidoylC₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₁₋₂amino, —CO₂(C₀₋₁₀ alkyl), —SO₂CF₃, —SO₂CF₂H, —SO₂CH₂CF₃, hydroxy, —(C₁₋₁₀ alkyl)OH, C₁₋₁₀ alkoxyC₀₋₁₀ alkyl, cyano, (C₁₋₆alkyl)cyano, and C₁₋₆haloalkyl, wherein R⁴ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents, and two R⁴ together with the ring atom to which each is attached optionally may form a saturated ring.
 4. A compound according to claim 3, wherein R⁴ is selected from tert-butylcarbonyl, methoxycarbonyl, methylcarbonyl, cyclopropylmethyl, cyclopropylmethylcarbonyl, cyclopropylethylcarbonyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyloxycarbonyl, isopropyloxycarbonyl, phenylmethyl, phenylpropyl, phenylmethylcarbonyl, phenylethylcarbonyl, phenyloxycarbonyl, phenylcarbonyl, oxazolylmethyl, 1,3-oxazolylmethyl, indolylmethyl, 1-phenylethyl, pyridinylmethyl, cyclohexylcarbonyl, fluoro, 2,2,2-trifluoroethyl, ethyl, 2-hydoxyethyl, neopentylcarbonyl, neopentyloxycarbonyl, ethylcarbonyl, ethyloxycarbonyl, methoxymethylcarbonyl (methylamino)methylcarbonyl, 2,3-dihydro-1H-indenylcarbonyl, pyrrolidinylmethylcarbonyl, tetrahydro-2H-pyranylcarbonyl, tetrahydro-2H-thiopyranyloxycarbonyl, tetrahydro-2H-pyranyloxycarbonyl, 1-(pyridinyl)ethyloxycarbonyl, adamantylcarbonyl, tetrahydrofuranyloxycarbonyl, trifluoroethylsulfonyl, dimethylamino, tert-butyloxycarbonyl, methyl, tert-butylaminocarbonyl, aminocarbonyl, azetidinyl, cyclohexylamino, oxo, hydroxy, methylaminocarbonyl, cyclopropylsulfonyl, methoxy, phenylamino, pyridinyl, hydroxyisopropyl, hydroxyeth-2-yl, trifluoromethyl, 2-(methylthio)eth-2-ylcarbonyl, methylsulfonyl, ethylcarbonyl, methylamino, isopropyloxycarbonyl, and hydroxyisopropyl; wherein R⁴ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents, and wherein two R⁴ together with the ring atom to which each is attached optionally may form a saturated ring.
 5. A compound according to claim 4, wherein embodiment R⁵ is selected from: methoxycarbonyl, tert-butylsulfonyl, tert-butylsulfamoyl, tert-butyl(methyl)sulfamoyl, tert-butyl(ethyl)sulfamoyl, pentafluorosulfanyl, methoxy, dimethyamino, oxo, amino, fluoro, isobutyl, isopropyl, sulfamoyl, dimethylsulfamoyl, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, tert-butyloxycarbonyl(1-methyl)ethyl, diethylsulfamoyl, ethylsulfamoyl, pyrrolidinylsulfonyl, methyl, tert-butylaminomethyl, methylaminocarbonyl, methylaminomethyl, ethyl, (1-hydroxy)ethyl, piperidinylsulfonyl, piperidinyl, thiomorpholinylcarbonyl, thiazolidinylcarbonyl, thiomorpholinylmethyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, ethylaminocarbonyl, morpholinylcarbonyl, tert-butyl, cyclopentylmethyl, cyclohexyl, cyclohexylsulfonyl, cyclohexylsulfamoyl, cyclopentyl, cyclopentylsulfonyl, benzyl, hydroxymethyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octane-3carbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, ethoxycarbonyl(dimethyleth-2-yl), hydroxy, trifluoromethyl, azetidinylsulfonyl, cyclopropylsulfonyl, cyclopropyl, chloro, ethylaminomethyl, pyrrolidinylmethyl, 1-pyrrolidin-1-ylethyl, cyclopropylmethyl, pyrazolylmethyl, morpholinylsulfonyl, isopropylaminomethyl, pyrazolyl, pyrrolidinyl, piperadinyl, methylsulfonyl, isopropylsulfonyl, isopropylsulfamoyl, methylsulfamoyl, benzylsulfamoyl, cyclopropylmethyl, cyclobutyl, tert-butylsulfonyl, tert-butyloxycarbonyl, tert-butyloxycarbonylmethyl, methoxymethyl, 2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl, methoxyeth-2-yl, triazolylmethyl, 1,2,3-triazolylmethyl, aminomethyl, ethylaminomethyl, aminocarbonyl, morpholinyl, isopropyl, isopropyl(methy)sulfamoyl, sulfonyl, cyano, 2,2,2-trifluoroethyl, ethylaminocarbonyl, tert-butylaminomethyl, isopropyloxycarbonyl(dimethyleth-2-yl), 1,1,1-trifluoro-3,3-dimethylbut-2-yl, (1,1,2-trimethylpropyl)sulfonyl, (1,1-dimethylpropyl)sulfonyl, isopropylsulfonimidoyl methylsulfonyl, ethylcarbonyl, 2,3-dihydro-1H-indenyl, ethylmethylsulfamoyl, neopentyl, methylaminomethyl dimethylamino, 2-(isopropylamino)propan-2-yl, 2,2-dimethylpropyl, hydroxymethyl, hydroxyeth-2-yl, tert-butyloxycarbonyl(2-methylprop-2-yl), methoxy, ethylaminocarbonyl, methylaminocarbonyl, and methoxymethyl; and wherein R⁵ is optionally substituted with 0, 1, 2, 3, or 4 R⁶ substituents.
 6. A compound according to claim 5, wherein A is selected from phenyl, methyl, ethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, isoindolinyl, benzo[d]thiazolyl,

2,3-dihydro-1H-indenyl, quinolinyl, pyridinyl, and indolinyl.
 7. A compound of claim 1 or a pharmaceutically acceptable salt, or a stereoisomer thereof selected from: tert-butyl 3-(cyanomethyl)-3-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-[3-(ethylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{3-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-[3-(cyclobutylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; tert-butyl 3-(cyanomethyl)-3-[3-(ethylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]azetidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-[3-(methylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; tert-butyl 3-(cyanomethyl)-3-[3-(cyclopropylamino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]azetidine-1-carboxylate; tert-butyl 3-(cyanomethyl)-3-(4-oxo-3-((2-(trifluoromethyl)pyridin-4-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; tert-butyl 3-(cyanomethyl)-3-(3((4(methoxycarbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; tert-butyl 3-(cyanomethyl)-3-(3-((4-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-[4-oxo-3-({4-[2,2,2-trifluoro-hydroxyethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{4-oxo-3-[(4-sulfamoylphenyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-{[1-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-5-yl]amino}-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-3-fluoro-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{3-[(2-methyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-{[4-(pentafluorosulfanyl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-{[4-(trifluoromethyl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-3-fluoro-4-{3-[(2-methyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-3-methyl-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-((1-oxo-2,3-dihydro-1H-inden-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1- carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-{[3-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-3-fluoro-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-{[4-(dimethylsulfamoyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluoropiperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-3-fluoro-4-[4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-3-fluoro-4-[4-oxo-3-({4-[2,2,2-trifluoro-1-hydroxyethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; tert-butyl 4-{3-[(2-tert-butyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate; tert-butyl 4-{3-[(2-tert-butyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-{[1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1,2-benzisothiazol-5-yl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluoropiperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 2-(4-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)acetonitrile; 2-(3-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 4-((1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 2-(3-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; methyl 5-(cyanomethyl)-5-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2- carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 3-(cyanomethyl)-3-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)azetidine-1-carboxylate; tert-butyl 3-(cyanomethyl)-3-{3-[(2-fluoropyridin-4-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}azetidine-1-carboxylate; tert-butyl 3-(cyanomethyl)-3-[4-oxo-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]azetidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 5-(3-((4-1-amino-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-(phenylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; N-(tert-butyl)-4-((1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzenesulfonamide; 2-(1-(2,2-difluoropropanoyl)-4-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; N-(tert-butyl)-4-((1-(4-(cyanomethyl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; 2-(4-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(2,2-difluoropropanoyl)piperidin-4-yl)acetonitrile; tert-butyl 4-(3-(3,5-bis((1H-pyrazol-1-yl)methyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-(3,5-dimethylphenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(3-(3,5-bis((1H-1,2,3-triazol-1-yl)methyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(3-(3,5-bis((2H-1,2,3-triazol-2-yl)methyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(3-(3-((1H-1,2,3-triazol-1-yl)methyl)-5-((2H-1,2,3-triazol-2-yl)methyl) phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(3-(m-toluidino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-(isoindolin-5-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-{[2-(cyclopropylmethyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{3-[(2-ethyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-[3-[(2-methyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; methyl 4-{3-[(2-tert-butyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; methyl 4-{3-[(2-ethyl-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl)amino]-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-{[2-(2-methylpropyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-{[2-(cyclopropylmethyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-{[2-(cyclopentylmethyl)-1,1-dioxo-2,3-dihydro-1,2-benzothiazol-5-yl]amino}-4-oxo-1H,4H,5H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-[4-oxo-3-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-{[4-(methylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{3-[(2-fluoropyridin-4-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; 4-(1-(1-(cyanomethyl)cyclohexyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-ylamino)-N,N-dimethylbenzenesulfonamide; 2-(1-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile; tert-butyl 4-(cyanomethyl)-4-(3-((1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 2-(8-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1,4-dioxaspiro[4.5]decan-8-yl)acetonitrile; 4-({1-[1-(cyanomethyl)-2-fluorocyclohexyl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; {2-fluoro-1-[4-oxo-3-({4-[2,2,2-trifluoro-1-hydroxy-1-methylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]cyclohexyl}acetonitrile {2-fluoro-1-[3-({4-[(1-methylethyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]cyclohexyl}acetonitrile; 2-(1-(3-((4-(1-amino-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; tert-butyl 5-(3-((4-(N-(tert-butyl)-N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(N-isopropyl-N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(N-ethyl-N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((1,1-dioxido-2-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(N-methylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((4-((1H-1,2,3-triazol-1-yl)methyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((4-((2H-1,2,3-triazol-2-yl)methyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(cyclopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((2-(tert-butyl)-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-cyclohexyl-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H- pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-cyclopentyl-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((4-(1-amino-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; [3-(3-{[4-(azetidin-1-ylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; {3-[3-({4-[(3-methylazetidin-1-yl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; {3-[3-({4-[(2,2-dimethylpyrrolidin-1-yl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; [3-{3-[(4-{[2-methylazetidin-1-yl]sulfonyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; {3-[4-oxo-3-({4-[2,2,2-trifluoro-1-hydroxy-1-methylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; ethyl 3-(4-((1-(3-(cyanomethyl)tetrahydro-2H-pyran-3-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)phenyl)-4,4,4-trifluoro-3-hydroxy-2,2-dimethylbutanoate; 2-(3-(3-((4-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((4-(3-fluoropyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((4-(3-methoxypyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((4-(3-methoxypyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((1-hydroxy-2,2-dimethyl-1-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(1-(3-((2-(tert-butyl)-1, 1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; 2-(1-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; 4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzonitrile; 2-(1-(4-oxo-3-((1-oxo-1,3-dihydroisobenzofuran-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; (1-{3-[(3,3-dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}cyclopentyl)acetonitrile; tert-butyl 4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzoate; 4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzamide; 2-(1-(3-((2-isopropyl-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; 4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-isopropylbenzenesulfonamide; 4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; 2-(1-(3-((4-(azetidin-1-ylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; 2-(1-(3-((4-(ethylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; N-(tert-butyl)-4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; N-(tert-butyl)-4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-ethylbenzenesulfonamide; 4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-diethylbenzenesulfonamide; tert-butyl 2-(4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylphenylsulfonamido)-2-methylpropanoate; 2-(1-(4-oxo-3-((1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclopentyl)acetonitrile; ethyl 2-(4-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylphenylsulfonamido)-2-methylpropanoate; tert-butyl 2-(5-((1-(1-(cyanomethyl)cyclopentyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-1-oxoisoindolin-2-yl)-2-methylpropanoate; methyl 4-(cyanomethyl)-4-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-((1-hydroxy-1-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-((4-cyanophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-((4-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(4-oxo-3-(quinolin-6-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; 2-(2-fluoro-1-(3-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(2-fluoro-1-(3-((2-fluoropyridin-4-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-2-fluorocyclohexyl)acetonitrile; 2-(2-fluoro-1-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1- yl)cyclohexyl)acetonitrile; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(thiazolidine-3-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(2-methylthiazolidine-3-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(2-methylthiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxy-4-isopropoxy-3,3-dimethyl-4-oxobutan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((1-hydroxy-2,2-dimethyl-1-(trifluoromethyl)-2,3-dihydro-1H-inden-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxy-3,3-dimethylbutan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(1,1,1-trifluoro-2-methoxypropan-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; {1-[3-({4-[1-(ethylamino)-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-2-fluorocyclohexyl}acetonitrile; [2-fluoro-1-{3-[(4-{1-methyl-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1- yl}cyclohexyl]acetonitrile; {1-[3-({4-[1-amino-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]-2-fluorocyclohexyl}acetonitrile; [3-{3-[(2-tert-butyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; {3-[3-({4-[(1-methylethyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; 4-({1-[3-(cyanomethyl)-4-fluorotetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; N-tert-butyl-4-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N-methylbenzenesulfonamide; [3-(3-{[4-(tert-butylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; N-tert-butyl-4-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)benzenesulfonamide; tert-butyl[5-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-1,1-dioxido-1,2-benzisothiazol-2(3H)-yl]acetate; tert-butyl 3-{[4-({1-[3-(cyanomethyl)tetrahydro-2H-pyran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)phenyl]sulfonyl}-3-methylbutanoate; {3-[3-({4-[1-amino-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; {3-[3-({4-[1-(tert-butylamino)-2,2,2-trifluoroethyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; [3-(3-{[4-(cyclopentylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; {3-[4-oxo-3-({4-[(1,1,2-trimethylpropyl)sulfonyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; [3-(3-{[4-(cyclohexylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; tert-butyl 5-(3-((4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5- (cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; {3-[3-({4-[(1,1-dimethylpropyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; [3-{3-[(2-cyclopentyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; {3-[4-oxo-3-({4-[2,2,2-trifluoro-1-pyrrolidin-1-ylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; {3-[4-oxo-3-({4-[1-pyrrolidin-1-ylethyl]phenyl}amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; {3-[3-({4-[(2,2-dimethylcyclopentyl)sulfonyl]phenyl}amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl]tetrahydro-2H-pyran-3-yl}acetonitrile; tert-butyl 5-(cyanomethyl)-5-(3-((4-(morpholinosulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; [3-(3-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl]acetonitrile; [3-{4-oxo-3-[(4-{2,2,2-trifluoro-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; tert-butyl 5-(cyanomethyl)-5-(3-((4-(1-(ethylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-(isopropylamino)ethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(1-(pyrrolidin-1-yl)ethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H- pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(1-(dimethylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-(quinolin-6-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-cyanoquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-methylquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(1H-pyrazol-1-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(2,2-dimethylmorpholine-4-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-(quinolin-3-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-(dimethylamino)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((2-carbamoylquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; 2-(3-(4-oxo-3-((4-(1-(trifluoromethyl)cyclopropyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((2-(dimethylamino)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((2-methylquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; tert-butyl 5-(cyanomethyl)-5-(3-((2-morpholinoquinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-(2-methylmorpholino)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(propan-2-yl-sulfonimidoyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; 2-(3-(4-oxo-3-((4-(propan-2-ylsulfonimidoyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 4-({1-[1-(cyanomethyl)-2-fluorocyclohexyl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; tert-butyl 5-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(cyclopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(isopropylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-(dimethylcarbamoyl)quinolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; 4-({1-[3-(cyanomethyl)tetrahydrofuran-3-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)benzonitrile; [3-{3-[(4-chlorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydrofuran-3-yl]acetonitrile; [3-{3-[(4-chloro-8-fluoroquinolin-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydrofuran-3-yl]acetonitrile; [3-{3-[(4-fluoroquinolin-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydrofuran-3-yl]acetonitrile; 2-(3-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydrofuran-3-yl)acetonitrile; 2-(3-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydrofuran-3-yl)acetonitrile; 2-(4-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-4-yl)acetonitrile; 2-(4-(3-((4-(tert-butylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-4-yl)acetonitrile; N-(tert-butyl)-4-((1-(4-(cyanomethyl)tetrahydro-2H-pyran-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N-methylbenzenesulfonamide; 4-((1-(4-(cyanomethyl)tetrahydro-2H-pyran-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 2-(4-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; 2-(3-fluoro-4-(3-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-tetrahydro-2H-pyran-4-yl)acetonitrile; 2-(4-(3-((2-(tert-butyl)-1-oxoisoindolin-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; 2-(3-fluoro-4-(3-(3-methyl-4-(thiomorpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-tetrahydro-2H-pyran-4-yl)acetonitrile; 2-(3-fluoro-4-(4-oxo-3-((4-(2-(trifluoromethyl)piperidin-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-4-yl)acetonitrile; 2-(4-(3-((4-(1-(tert-butylamino)-2,2,2-trifluoroethyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; 2-[4-(3-{[1,1-dioxo-2-(piperidin-4-yl)-3H-1,2-benzothiazol-5-yl]amino}-4-oxo-5H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorooxan-4-yl]acetonitrile; tert-butyl 4-(cyanomethyl)-3-fluoro-4-{3-[(4-{1-methyl-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(2-(isopropylamino)propan-2-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 4-(cyanomethyl)-3-fluoro-4-(3-{[4-(1-methoxyethyl)phenyl]amino}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{3-[(4-{1-methyl-1-[(1-methylethyl)amino]ethyl}phenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; 2-(4-(3-((1,1-dioxido-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-fluorotetrahydro-2H-pyran-4-yl)acetonitrile; tert-butyl 4-(cyanomethyl)-3-fluoro-4-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(3-((4-(1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-((4-(3-(trifluoromethyl)pyrrolidin-3-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(3-(trifluoromethyl)pyrrolidin-3-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(2-(trifluoromethyl)piperidin-2-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-((4-(((2,2,2-trifluoroethyl)amino)methyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(N-isopropylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(3-((4-(N-benzylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(N-(cyclopropylmethyl) sulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(N-(2-methoxyethyl)sulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(N-cyclohexylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-((4-(piperidin-1-ylsulfonyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1- carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(morpholinosulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((3-fluoro-4-(N-isopropylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(N-(cyclopropylmethyl)sulfamoyl)-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; (4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl)acetonitrile; [1-(cyclopropylcarbonyl)-4-{3-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}piperidin-4-yl]acetonitrile; 4-({1-[1-benzyl-4-(cyanomethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(4-methylbenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-[(1-{4-(cyanomethyl)-1-[4-(trifluoromethyl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; 4-[(1-{4-(cyanomethyl)-1-[4-(1-methylethyl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; 4-[(1-{4-(cyanomethyl)-1-[4-(1-methylethyl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzene sulfonamide; 4-[(1-{4-(cyanomethyl)-1-[4-(1methylethoxy)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzene sulfonamide; 4-({1-[4-(cyanomethyl)-1-(4-fluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(3-fluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzene sulfonamide; 4-({1-[4-(cyanomethyl)-1-(2-fluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(2,6-difluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzene sulfonamide; 4-({1-[4-(cyanomethyl)-1-(2,3,6-trifluorobenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(1,3-oxazol-2-ylmethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(4-isoxazol-3-ylbenzyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-[(1-{4-(cyanomethyl)-1-[4-(2-oxopyrrolidin-1-yl)benzyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3- yl)amino]-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(3-phenylpropyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzene sulfonamide; 4-({1-[4-(cyanomethyl)-1-(1H-indol-4-ylmethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-((1-(4-(cyanomethyl)-1-(1-(2,6-difluorophenyl)ethyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 4-((1-(4-(cyanomethyl)-1-phenethylpiperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 3-({1-[4-(cyanomethyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-propanoylpiperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(3,3,3-trifluoropropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(methoxyacetyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(N,N-dimethylglycyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(2,2-dimethylpropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(cyclopropylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-[(1-{4-(cyanomethyl)-1-[(3,3-difluorocyclobutyl)carbonyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]- N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(cyclohexylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-[(1-{4-(cyanomethyl)-1-[tricyclo[3.3.1.13,7]dec-1-ylcarbonyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(cyclopropylacetyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(3-cyclopropylpropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(phenylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-[(1-{1-[(4-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; 4-[(1-{1-[(3-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; 4-[(1-{1-[(2-chlorophenyl)carbonyl]-4-(cyanomethyl)piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-{[4-(trifluoromethyl)phenyl]acetyl}piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(3-phenylpropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(2,3-dihydro-1H-inden-2-ylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-[(1-{4-(cyanomethyl)-1-[(2-oxopyrrolidin-1-yl)acetyl]piperidin-4-yl}-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino]-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(3-cyanopropanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-({1-[4-(cyanomethyl)-1-(3,3-dimethylbutanoyl)piperidin-4-yl]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl}amino)-N,N-dimethylbenzenesulfonamide; 4-((1-(4-(cyanomethyl)-1-(2-(methylthio)propanoyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 4-((1-(1-(2-cyanoacetyl)-4-(cyanomethyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; methyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; phenyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 4-fluorophenyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; neopentyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; ethyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; isopropyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 2-methylcyclopentyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 2-(methylthio)ethyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tetrahydro-2H-thiopyran-4-yl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 1-methoxypropan-2-yl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tetrahydrofuran-3-yl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tetrahydro-2H-pyran-4-yl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 1,1,1-trifluoropropan-2-yl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 1-(pyridin-2-yl)ethyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 1-cyanoethyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tetrahydrofuran-3-yl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 2,2,2-trifluoroethyl 4-(cyanomethyl)-4-(3-((4-(N,N-dimethylsulfamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; isopropyl-4-(cyanomethyl)-4-(3-(2-fluoropyridin-4-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; methyl 4-(cyanomethyl)-4-(3-(2-fluoropyridin-4-ylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 4-((1-(4-(cyanomethyl)-1-((2,2,2-trifluoroethyl)sulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 4-((1-(4-(cyanomethyl)-1-(cyclopropylsulfonyl)piperidin-4-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; 6-(4-(cyanomethyl)-4-(3-((4(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; 6-(4-(cyanomethyl)-4-(3-((4((difluoromethyl)sulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; 2-(4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-1-(5 (trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; 6-(4-(cyanomethyl)-4-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; 6-((3R,4R)-4-(cyanomethyl)-3-fluoro-4-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-1-yl)nicotinonitrile; 2-(1-(5-iodopyridin-2-yl)-4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; 2-(1-(5-bromopyridin-2-yl)-4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; 2-(4-(3-(3-methyl-4-(thiomorpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; (R or S)-2-(4-(4-oxo-3-(4-(2,2,2-trifluoro-1-hydroxyethyl)phenylamino)-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; 2-(4-(3-(4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)-1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)acetonitrile; 2-(1-(2,2-difluoropropanoyl)-4-(3-((4-(methylsulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidin-4-yl)acetonitrile; 2-(4-(3-fluoroazetidin-1-yl)-1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; 2-(4-hydroxy-1-(4-oxo-3-((4-(trifluoromethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-methoxyazetidin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)acetonitrile; 2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-hydroxycyclohexyl)acetonitrile; 2-(1-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; 2-(4-(3-methoxyazetidin-1-yl)-1-(4-oxo-3-((4-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(1-(4-oxo-3-((4-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; 2-(4-(cyclohexylamino)-1-(4-oxo-3-((4-(trifluoromethoxy)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((4-chloro-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyclohexylamino)cyclohexyl)acetonitrile; 2-(1-(3-((4-chloro-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-methoxyazetidin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((4-chloro-3-fluorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(phenylamino)cyclohexyl)acetonitrile; 2-(1-(3-((4-((difluoromethyl)sulfonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)acetonitrile; 4-((1-(1-(cyanomethyl)-4-(3-fluoroazetidin-1-yl)cyclohexyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; 2-(4-(3-fluoroazetidin-1-yl)-1-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(4-(dimethylamino)-1-(3-((2-methyl-1,1-dioxido-2,3-dihydrobenzo-[d]isothiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(4-(3-fluoroazetidin-1-yl)-1-(3-((2-methyl-1,1-dioxido-2,3-dihy-drobenzo[d]isothiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)acetonitrile; 2-(1-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(dimethylamino)cyclohexyl)acetonitrile; 4-((1-(1-(cyanomethyl)-4-oxocyclohexyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide; N-(tert-butyl)-5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxamide; N-tert-butyl-5-{3-[(2-tert-butyl-1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-5-(cyanomethyl)-N-methyltetrahydro-2H-pyran-2-carboxamide; isopropyl 5-(3-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; 2-(3-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((3-methyl-4-(2-methylpiperidine-1-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((3-methyl-4-(2-methylpiperidine-1-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; 2-(3-(3-((4-(4-hydroxy-4-methylpiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-3-yl)acetonitrile; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(morpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(thiomorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(pyrrolidine-1-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(3-methylmorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(2,6-dimethylmorpholine-4-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((4-(ethyl(2,2,2-trifluoroethyl)carbamoyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((3-methyl-4-(methyl(2,2,2-trifluoroethyl)carbamoyl)phenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(3-((4-(2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(3-((2-methylbenzo[d]thiazol-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; [1-{3-[(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}-2-fluorocyclohexyl]acetonitrile; tert-butyl 5-(cyanomethyl)-5-(3-((3,3-dimethyl-2-oxoindolin-6-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran- 2-carboxylate; [3-{3-[(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; [3-{3-[(2-methyl-1,3-benzothiazol-6-yl)amino]-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl}tetrahydro-2H-pyran-3-yl]acetonitrile; tert-butyl 5-(cyanomethyl)-5-(3-((2-fluoropyridin-4-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 5-(cyanomethyl)-5-(4-oxo-3-((4-(2,2,2-trifluoro-1-methoxyethyl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)tetrahydro-2H-pyran-2-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-((4-(4,4-difluoropiperidine-1-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl-4-(3-((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-3-methylphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-{3-[(5-methyl-4-{3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl}cyclohexa-1,3,5-trien-1-yl)amino]-4-oxo-5H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate; tert-butyl-4-(cyanomethyl)-4-(3-(3-methyl-4-(thiomorpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl-4-(cyanomethyl)-4-(3-((1,1-dioxido-2-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-(4-(2-(trifluoromethyl)piperidin-2-yl)phenylamino)-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(4-oxo-3-(4-(2-(trifluoromethyl)pyrrolidin-2-yl)phenylamino)-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; tert-butyl 4-(cyanomethyl)-4-(3-(3-methyl-4-(morpholine-4-carbonyl)phenylamino)-4-oxo-4,5-dihydropyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate; 5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N-(methylsulfonyl)tetrahydro-2H-pyran-2-carboxamide; 5-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-5-(cyanomethyl)-N,N-dimethyltetrahydro-2H-pyran-2-carboxamide; and 2-(3-(3-((4-chlorophenyl)amino)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3-yl)acetonitrile.
 7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 8. A method for the treatment of a JAK-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable thereof.
 9. A method of treating a condition in a mammal that can be ameliorated by the inhibition of Janus kinases JAK1 and JAK 2 which condition is selected from, arthritis, asthma and obstructive airways diseases, autoimmune diseases or disorders, and cancer comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof.
 10. A method according to claim 10, wherein said condition is arthritis.
 11. A method according to claim 10, wherein said condition is selected from rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
 12. A method according to claim 10, wherein said condition is asthma or obstructive airways diseases.
 13. A method according to claim 13, wherein said condition is selected from: chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease (COPD), and emphysema.
 14. A method according to claim 10, wherein said condition is autoimmune diseases or disorders.
 15. A method of treating asthma in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 16. A method of treating arthritis in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 17. Use of a compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the treatment of a disease or a disorder ameliorated by the inhibition of Janus kinases JAK1 and JAK
 2. 18. Use of a compound of claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof and a second active agent in the manufacture of a medicament for the treatment of a disease or a disorder ameliorated by the inhibition Janus kinases JAK1 and JAK
 2. 